Deliverable D1.8. AWP Y3 including PARC Project Portfolio WP1 – T1.1

DELIVERABLE D1.8 P-A-R-C HORIZON-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 Partnership for the Assessment of Risks from Chemicals Deliverable D1.8. AWP Y3 including PARC Project Portfolio WP1 – T1.1 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 1 PU = Public PP = Restricted to other programme participants (including the Commission Services) RE = Restricted to a group specified by the consortium (including the Commission Services) CO = Confidential, only for members of the consortium (including the Commission Services) 1 On date 05/03/2024, the Project Officer has requested that the deliverable D1.8 with title "AWPY3 including rolling SRIA " was renamed "AWP Y3 including PARC Project Portfolio”, according to the ongoing amendment. D1.8 was resubmitted on 28 March 2024 with the new title, once the amendment was officially adopted on 26 March 2024. Technical reference Work package WP1 - Coordination and Management Task T1.1 - Overall executive management and support of the Partnership Dissemination level 1 PU Lead Beneficiary/ Responsible AE ANSES Contributing Participants All PARC participants Responsible author(s) Pascal Sanders, ANSES, [email protected], Christophe Rousselle, ANSES, [email protected] Co-authors PARC Coordination Team, ANSES, [email protected], WP coleaders, Task co-leaders Reviewers PARC Coordination Team, ANSES, [email protected], WP coleaders, Task co-leaders Due date of deliverable 31/12/2023 Actual submission date 29/02/2024 Second submission date1 28/03/2024 Third submission date 10/07/2024 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 3 Document history Version Date Reviewer name/Institutions Short description of changes 1 17/10/2023 WP co-leaders and Task coleaders in close collaboration with the Project managers and partners involved in their WPs and Tasks First draft with modifications in track changes 2 31/10/2023 WP co-leaders and PARC CT only Review of the first draft 3 18/12/2023 WP co-leaders and Task coleaders in close collaboration with the Project managers and partners involved in their WPs and Tasks Second draft with modifications in track changes 4 05/01/2024 WP co-leaders and PARC CT only Review of the second draft 5 16/02/2024 Project managers, taks coleaders and WP co-leaders Update of the project description based on HaDEA’s recommandations 6 29/02/2024 PARC CT Review of the final draft and submission to HaDEA 7 27/03/2024 PARC CT As requested by the Project Officer, the title of D1.8 was modified in “AWPY3 including PARC Project Portfolio” D1.8 was resubmitted once the amendment was officially approved in March 2024 8 10/07/2024 PARC CT, Project managers, taks co-leaders and WP coleaders - Updated version of the AWPY3 submitted to answer HaDEA’s comments - Table 2.2.a updated with the correct number of PMs per partner for each WP for Y3 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 4 “Funded by the European Union. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them.” - Table 2.2.b updated with the correct total number of PMs per WP - Table 2.3.a updated with the total effort per partner per WP for Y3 - Table 2.3.b updated with the correct cost items for Y3 for some partners - Table 2.3.c updated with the correct overview of planned budget for project and per WP DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 5 Abstract This Annual Work Plan (AWP) describes the activities to be implemented during the ‘PARC year’, including the updated Project Portfolio. The AWP covers the period from May 2024 to April 2025 (M25-M36) which are referred to as ‘PARC years’. Key Words Work Plan, Project Portfolio Period M25-M36 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 5 Table of contents Document history _______________________________________________________________________________ 3 Abstract __________________________________________________________________________________________ 5 Key Words _______________________________________________________________________________________ 5 Table of contents ________________________________________________________________________________ 5 List of abbreviations ____________________________________________________________________________ 6 Structure of the Annual Work Programme ____________________________________________________ 8 1. Coherence with part B of the proposal ___________________________________________________ 8 1.1 Annual Work Plan (AWP) objectives __________________________________________________ 8 1.2 Expected impacts______________________________________________________________________ 10 1.3 Correspondence with part B of the proposal _______________________________________ 15 1.4 Update of the PARC Project Portfolio ____________________________________________________ 15 2. Annual Work Programme Activities ____________________________________________________ 20 2.1 Annual Work Programme ____________________________________________________________ 20 2.1.1 Structure of the Annual Work Programme __________________________________________ 20 2.1.2 Timing of the different programmed activities and their components ______________________ 20 2.2 Detailed work description ________________________________________________________________ 20 Table 2.2.a: Annual Work Programme Activities for each set of activities _______________________ 20 Table 2.2.b: AWP Set of Activities ____________________________________________________ 115 Table 2.2.c: Additional Deliverables List _______________________________________________ 116 2.3 Resources to be committed _____________________________________________________________ 120 Table 2.3.a: Summary effort table ____________________________________________________ 120 Table 2.3.b: Other major cost items (travel, equipment, infrastructure, goods and services) ________ 128 Table 2.3.c: Overview of planned budget per project and per Work Package ___________________ 142 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 6 List of abbreviations AA: Anti-Androgenicity ADME: Absorption, Distribution, Metabolism and Excretion AE: Affiliated Entity AO/ AON/ AOP: Adverse Outcome/ AO Network/ Pathway API: Application Programming Interfaces ASR/ AWPs: Annual Summary Report/Work Plans BBB: Blood Brain Barrier BCSFB: Blood-cerebrospinal Fluid Barrier BMD: Benchmark dose BPR: Biocides Products CA: Consortium Agreement CEC: Chemicals of Emerging Concern CG: Core Group CL/ ML: Chemical Leader/ Methodology Leader CLP: Classification, Labelling and Packaging CMS: Content Management System COPCSD: Common Open Platform on Chemical Safety Data CPDC: Common Platform for Data on Chemicals CPR: Cosmetic Products CSS: Chemicals Strategy for Sustainability CT: ANSES PARC Coordination Team DILI: Drug-Induced Liver Injury DEPB: Data and Ethics Protection Board DMP: Data Management Plan DNT/ANT: Developmental and Acute Neurotocixity DoA: Description of Action EATS: Estrogen, Androgen, Steroidogenesis, and Thyroid EBD: Environmental Burden of Disease EC: European Commission ECHA: European Chemicals Agency ED/ EDCs: Endocrine Disrupters / endocrine disrupting compounds MIEs: Molecular Initiating Events MoA: Mode of Action MS: Member States MTA: Material Transfer Agreement MRA: Mixture Risk Assessment NAMs: New Approach Methodologies NGRA: Next Generation Risk Assessment NGTxC: Non-Genotoxic Carcinogens NHs: National Hubs NHCs: National Hub Coordinators NHCPs: National Hub Contact Points NTS: Non-Targeted Screening OECD: Organisation for Economic Co-operation and Development OO: Operational Objectives OSOA: One Substance One Assessment PDB: Protein Data bank PFAS: perand polyfluoroalkyl substances PFDP: PARC FAIR Data Policy PBK: Physiologically Based Kinetic PBMC: Peripheral Blood Mononuclear Cells PBPK: Physiologically Based Pharmacokinetic PBTK: Physiologically Based Toxicokinetic PM: Project Manager PMT: Persistent Mobile and Toxic PoC: Prof of Concept POD: Point of Departure POP: Persistant Organic Pollutant PPPR: Plant Protection Products PT: Proficiency Testing QA/QC: Quality Assurance / Quality Control QAWG: Quality Assurance Working Group DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 7 EDA: Effect-Directed Analysis EFSA: European Food Safety Authority EOSC: European Open Science Cloud ERA: Environmental Risk Assessment EWS: Early Warning System FAIR: Findable, Accessible, Interoperable, and Reusable FIP: FAIR Implementation Profiles FIT: FAIR Implementation Taskgroup GA: Grant Agreement GB: Governing Board GDPR: General Data Protection Regulation GFF: Go Fair Foundation GIVIMP: Good In Vitro Methods Practices GS: Grant Signatory GSB: Grant Signatory Board HA: Hazard Assessment HBM: Human BioMonitoring HBM GV: Health-based Guidance Values HRMS: High Resolution Mass Spectrometry IATA: Integrative Approaches for testing and Assessment IB: International Board IPR: Intellectual Property Rights IVIVE: in vitro - in vivo extrapolation JRC: Joint Research Centre KIC: Knowledge and Innovation Communities KEs: Key Events KERs: Key Event Relationships LCA: Life-cycle assessment MAF: Mixture Assessment Factor MB: Management Board MCRA: Monte Carlo Risk Assessment QIVIVE: Quantitative in vitro / in vivo Extrapolation QSAR: Quantitative Structure Activity Relationship RA/RM: Risk Assessment / Risk Management R&I: Research and Innovation RRM: Rapid Response Mechanism SCCS: Scientific Committee on Consumer Safety SDGs: Sustainable Development Goals S2PD: Science-to-Policy Dialogue SAICM: Strategic Approach to International Chemicals Management SF: Stakeholder Forum SG: Specialty Group SO: Specific Objectives SPM: Suspended Particulate Matter SRIA: Strategic Research and Innovation Agenda SS: suspect screening SSbD: Safe-and-Sustainable-by-Design SSO: Single-Sign-On SOP: Standard Operating Procedures SVM: Support Vector Machine T/TL: Task/Task co-leaders TTC: Toxicological Threshold of Concern THSD: Thyroid Hormone System Disruptors TKTD: Toxicokinetic-toxicodynamic modelling UCWG: Use Case Working Group(s) UNEP: United Nations Environment Programme US-EPA: US Environmental Protection Agency US-NTP: US National Toxicology Program WHO: World Health Organization WoE: Weight-of-Evidence WP/ WPL: Work Package / WP co-leaders WWTP: Wastewater treatment plants DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 8 Structure of the Annual Work Programme 1. Coherence with part B of the proposal 1.1 Annual Work Plan (AWP) objectives The objectives of this third year are aligned with the specific objectives of PARC. SO1 - To achieve a high scientific policy and societal impact, EU and national risk assessors and regulatory entities come together with the scientific community in a crossdisciplinary network to set priorities for research and innovation in chemical risk assessment OO1-Maintaining a high management level through meeting of Boards. For the year 3 a consortium meeting will be organised on 13-16 May 2024, to review our progress, support discussion on new priorities established during the 2nd Semester of Y2 based on the mapping of needs. OO2-National hubs will continue their activities to gather national needs, encourage cooperation and identify potential synergies. OO3-Based on the work done during Y2 on the priorisation process and review of needs, the review of new projects and monitoring on on-going ones will be performed. OO4-Using PARCopedia, launched Y2, the chemical risk assessment community will find, cocreate and discuss knowledge on all matters related to chemical risk assessment and Next Generation Risk Assessment (NGRA). The roadmap towards the uptake of NGRA into European chemicals legislation will be finalised with a broad range of relevant parties. Chemical and Method leaders will follow and report on the work developed within PARC. OO5-Cooperation with other programmes and initiatives will be encouraged. The first SYNnet Forum will be organized back-to-back with a relevant scientific event. OO6Communication and dissemination of knowledge produced by PARC will be performed via the website, the open access to scientific publications. SO2 - European and national risk assessment entities and their scientific networks carry out a joint research and innovation programme to respond to the agreed priorities in chemicals risk assessment. OO7-Work programme. The programme will be monitored and six new projects started in Y3. Several on-going projects will continue to perform their testing and modelling activities to generate data. OO8-Innovative concepts, models and tools. Some reports will be delivered end of Y3 on the work done on new approach methodologies, integrative approaches for testing and assessment (IATA) and physiologically based models (PBK) Reports on aggregate exposure for general DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 15 OO13: Build capacities by developing and carrying out training and exchange programmes in chemical RA WP4 - P4.1.1.4.d; P4.1.4.2.a; P4.3.1.c; P4.3.2.b; P4.3.4.a; WP5 - P5.2.1.b; WP6 - P6.2.1.a; P6.2.1.b; P6.2.3.a; P6.2.4.b; P6.2.4.d; P6.3.1.a; P6.3.1.b; P6.3.2.a; P6.4.2.b; P6.4.4.d; WP7 - P7.2.2.b; WP9 – T9.1; T9.4; * = Projects starting Y3. 1.3 Correspondence with part B of the proposal For this third AWP, the actions initiated in the form of projects, case studies and those activities corresponding to recurrent tasks are presented by WP and tasks using the structure described in Part B. AWPY3 has been designed to be intrinsically linked and complementary to the sevenyear activity plan (Description of Action or DoA). It will provide the necessary basis on which to continue building the Partnership in the following years. This is true for the specific challenges, the scope of PARC as well as for the activities that will be initiated during the third year of PARC. 1.4 Update of the PARC Project Portfolio The PARC Project Portfolio constitutes an overview of the PARC Projects, providing detailed information on timelines, outputs, etc. The PARC Project Portfolio is administered by the Coordinator and updated each year to integrate new Projects and follow those that have been implemented. It serves as a basis for the preparation of the AWP. The Project Portfolio annexed to this 3rd AWP is a compilation of all projects' summaries concerned that are already implemented and those additional ones that have been proposed and reviewed under task 2.1 and validated to start during the 3rd year of PARC. Table 1.2: New projects Year 3 Project ID Schedule P4.2.c_Y3_Human exposure_INERIS_AU M25-M72 P4.3.2.c_Y3_H03-Complementarydevelopments_JSI M25-M72 P5.1.1.c_Y3_TG+ EnnB1_ANSES M25-M60 P6.3.2.a_Y1_ToolsRA_CS20_Y3_PESTNAM_ISS M25-M48 P6.4.1.c_Y3_Skinsenmix_RegionH M25-M72 P6.4.3.b_Y3_ENFORCE_KemI M25-M72 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 16 Table 1.3: Projects and case studies planned to end Year 3 In bold, projects initially planned to end M36 that have been extended Project ID Schedule Comments Rationale for projects that have been extended P4.1.1.4.a_Y1_OccupFeasability_TTL M1-M29* *The project has been extended from M18 to M29 The coding of occupations (according to ISCO codes) and transfer of coded information to PEH platform (allowing the transfer of data for statistical analysis) is taking more time than anticipated and is planned to occur only now in November-December 2023. Therefore, an extension of the deadline was applied. Impact on AD4.8 (postponed from M18 to M29) P4.1.1.4.b_Y1_SentinelSystem_KULeuven M1-M36* *This project up to M81 has been broken down at M36 to assess what has been achieved. P4.1.3.1.a_Y1_DerivationofHBM-GVs_UBA M1-M36* *This project up to M81 has been broken down at M36 to assess what has been achieved. P4.1.4.2.a_Y1_DataAnalysisHBM4EU_VITO M1-M36 Discussions on the need for an extension are ongoing P4.2.a_Y1_ENVMonitoringPilotSurvey_INERIS_AU M1-M36 P4.3.1.b_Y1_T02-QAQC_WR M1-M60* *The project has been extended from M36 to M60 The project has experienced a significant delay regarding the start of actual activities. Moreover, During the T4.3 meeting in Paris 9.10.2023, additional topics were identified to be included in P4.3.1.b_T02 (development of common mixture(s) of QAQC markers for harmonized method performance assessment, and development of strategies for improving the semiquantitative performances obtained with screening approaches). Therefore, an extension was applied to allow to finetune generic guidance documents to be drafted in P4.3.1.b_T02 based on experiences and lessons learned from a pilot project that is starting in T4.2 P4.3.3.a_Y1_E01-Wastewater based epidemiology_UFZ-UBATH M1-M48* *The project has been extended from M36 to M48 The results of this project will serve as a proof-of-concept, illustrating the effectiveness of innovative sampling tools and the integration of suspect and non-target screening. The ambition of this study requires new, cuttingedge tools as well as coordinated actions focused on sampling / analysis / data mining. To enable these, and to maintain an inclusive nature of the project (an extended number of laboratories to take part) and to maintain DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 17 quality of outputs, the project needs strong coordination, planning as well as a robust interlaboratory study. Also, an in-depth evaluation of the obtained large data sets using state-of-the-art statistical methods and a thorough interpretation should be achieved within the project time. Therefore, one year extension will provide opportunity to deliver this ambitious project with maximum output and impact with an extra assurance of the highest possible quality. Impact on D4.2 (postponed from M36 to M48) P5.1.1.a_Y1_Toxins_BfR_UNIVIE M1-M48* *The project has been extended from M36 to M48 There was some delay on substance procurement (natural toxins) and on hiring personal. Therefore, an extension of one year was applied. Impact on D5.11 (shifted from M60 to M54) P5.1.1.b_Y1_BPA_HumTox_BfR M1-M54* *The project has been extended from M36 to M54 There was some delay on substance centralize order (BPA alternative) and on hiring personal. Therefore, an extension of one year was applied. Impact on D5.11 (shifted from M60 to M54) P5.1.2.a_Y1_NaturalToxinsAqua_UGent M1-M36 P5.2.1.b_Y1_MD-EDC_INRAE M1-M48* *The project has been extended from M36 to M48 There was some delay on substance centralize order and on hiring personal. Therefore, an extension of one year was applied. Impact on D5.5 (shifted from M36 to M48) P5.2.1.d_Y1_Immunotox_Inserm M1-M48* *The project has been extended from M36 to M48 COVID-19 vaccination study was planned but did not get the money until 2023. In Y2 they got budget for this study. Moreover, there was some delay due to recruitment difficulties. Therefore, an extension of one year was applied. Impact on D5.5 (shifted from M36 to M48) P5.2.1.e_Y1_DNT-ANT_UFZ_IUF_UU M1-M48* *The project has been extended from M36 to M48 There was some delay on Neg/Pos controls centralized and on hiring personal. Therefore, an extension of one year was applied. Impact on D5.5 (shifted from M36 to M48) P5.3.1.a_Y1_SystemsToxicology_UL-LACDR M1-M48* *The project has been extended from M36 to M48 The start of case studies was delayed and there were some recruitment difficulties. Therefore, an extension of one year was applied. Impact on D5.7 (new title to englobe P5.3.1.a and P5.3.2.a). P5.3.2.a_Y1_AOPDevelopment_Inserm M1-M48* *The project has been extended from M36 to M48 There was some delay due to the organization of the workshop that has been postponed until June 23 for practical reasons. Moreover, most of the T5.2 projects will be delayed, and as P5.3.2.a relies on them for data, an extension of one year was applied. Impact on D5.7 (new title to englobe P5.3.1.a and P5.3.2.a). P5.3.4.a_Y1_PBK_Kinetics_Fraunhofer M1-M48* *The project has been extended from M36 to M48 There was some delay due to the organization of the workshop that has been postponed until June 23 for practical reasons. Moreover, most of the T5.1 and T5.2 projects will be delayed, and as P5.3.4.a relies on them for data, an extension of one year was applied. Impact on D5.2 (postponed from M24 to M36) DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 18 P6.1.1.a_Y1_HumanRelevance_RIVM M1-M36 Discussions on the need for an extension are ongoing P6.1.1.b_Y1_IATA-ED_UAntwerpen M1-M36 Discussions on the need for an extension are ongoing P6.1.1.c_Y1_IATA_GENTOX_Sciensano M1-M36 Discussions on the need for an extension are ongoing P6.1.1.d_Y1_IATA_STOT_UL-LACDR M1-M36 Discussions on the need for an extension are ongoing P6.2.1.a_Y1_SourcetoDose_VITO M1-M36 Discussions on the need for an extension are ongoing P6.4.1.a_Y1_OPREMIXCS1_BRUNEL_UGot M1-M40* *The project has been extended from M36 to M40 The projects started with an extensive delay, since it took longer as expected to get organised. The administrative effort and requirements of the projects were underestimated. Therefore, the extension would provide more time to scientifically conclude on the outcome of the case studies and provide a more overarching picture of the projects. Impact on AD6.17 and AD6.18 (postponed from M36 to M40) P6.4.1.b_Y1_MONAMMIXCS2_UFZ M1-M40* *The project has been extended from M36 to M40 P6.4.2.a_Y1_LandscapingSurv_UNIBAS M1-M36 P6.4.2.b_Y1_NGRApractice_VKM_NIPH M1-M36* *This project up to M81 has been broken down at M36 to assess what has been achieved. P6.4.2.c_Y1_NAMAM_UT M1-M36 P6.4.3.a_Y1_SuProM_MU M1-M36 P6.4.4.b_Y1_PPPEXPCS2_SLU M1-M36* *This project up to M81 has been broken up into 2 phases. The first phase was planned to end M24 but will be extended until M36 There was a delay due to a change of project manager. First results will be available in 2024 and presented to regulatory stakeholders with the intention to continue the research addressing relevant questions from stakeholders. Therefore, an extension of one year was applied for the first phase. P6.4.4.c_Y1_PPPEFFCS3_UFZ M1-M36* *This project up to M81 has been broken down at M36 to assess what has been achieved. P7.2.2.a_Y1_chemicals-in-environment_MU_VITO M1-M36 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 19 In bold, case studies initially planned to end M36 that have been extended Project ID Case Study ID Case Study Schedule Comments Rationale for case studies that have been extended P6.3.1.a_Y1_Substan ceRA_SU (M1-M48) CS12_MethodOSOA_SU M1-M42* *The case study has been extended from M36 to M42 Extended due to a delay related to to recruitment process of the PhD-student CS13_Plasticizers RA_UCL M1-M36* *The case study has been extended from M24 to M36 Extended due to a delay related to obtaining data P6.3.1.b_Y1_EffectR A_BPI (M1-M48) CS10_ED-cosmetics_VUB M8-M32 CS15_DNT_SU M1-M36 CS17_ED-in vitro_BPI M1-M48* *The case study has been extended from M36 to M48 Extended due to a delay related to handling overwhelming amounts of literature data CS18_ED-classes_BPI M1-M48* *The case study has been extended from M36 to year 4 (end M48) Extended due to a delay related to handling overwhelming amounts of literature data P6.3.2.a_Y1_ToolsRA _SU (M1-M48) CS1_CARB_SYKE M1-M36 CS2_RiskReduction_SU M1-M36* *The case study has been extended from M24 to M36 Extended due to a delay related to handling overwhelming amounts of literature and obtaining data CS3_WorkplaceRA_TTL M1-M36 CS7_REGPREP_EAWAG M1-M36* *First phase M1-M36 CS8_OccupReproDev_KI M1-M36 CS16_UncertaintyRA_ULUND M1-M36 CS19_DataGapFilling_KEMI-DTU M13-M30* *The case study has been extended from M24 to M30 Extended due to a delay related to recruiting students DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 20 2. Annual Work Programme Activities 2.1 Annual Work Programme 2.1.1 Structure of the Annual Work Programme The structure of the AWPY is based on the work packages (WP) description of transversal activities as well as more specific activities that are related to projects. 2.1.2 Timing of the different programmed activities and their components The third AWP will cover a duration of 12 months (M25-M36) from 1 May 2024 to 30 April 2025. All WPs will be active in Y3. 2.2 Detailed work description For all the WPs, the full description of work by projects is available in the PARC Project Portfolio in Annex II. The WP co-leaders have coordinated the writing for their WP with the Task co-leaders. Table 2.2.a: Annual Work Programme Activities for each set of activities WP N° WP1 Lead Beneficiary ANSES WP title Coordination and Management Part ner N° 1 1.1 1.2 1.4 1.13 2 3 3.1 4 4.2 5 6 7 8 10 10.1 11 12 13 14 15 16 17 18 20 20.4 20.6 21 22 24 25 26 26.4 26.6 27 29 29.1 30 31 32 33 34 34.5 35 35.7 35.8 35.9 36 36.2 50 59 61 Part ner shor t nam e ANSES INSERM INRAE INERIS EHESP SpF EAA AGES VITO DOMG SCIENSANO CIPH MOH-CY/SGL MU DEPA AU HB EEA THL TTL UBA BfR NCPHP UI ISS IUSS UNINA RSU NPHSL LNS RIVM NIPH NIVA NVI NIOM INSA APA SZU-SK JSI NIJZ CSIC ISCIII IISPV SEPA KEMI IVL SLV AUTH GCSL UKHSA UOB EPA PM/ part ner2 124.5 1 0.8 0.8 4 7.4 5.52 0.6 5.77 3.3 0.8 1.1 1.1 4.9 1.5 0.8 1.2 3 0.1 1.2 5.4 7.7 2.6 1.5 1.7 0.3 3.0 1.2 1 2.5 5.2 1.2 0.2 0.2 2.2 6 1 3.1 0.5 4.5 0.8 4.8 0.5 1.2 3.4 0.2 1 5.6 3 2 3 1.2 Star t M25 End M36 2 PMs have been allocated to the Grant Signatories for the management of their affiliated entities and their role of NHCP. In some cases, the Grant Signatories do not have any PM as they do not manage any AEs and are not NHCP in PARC. DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 21 Objectives The main goal of WP1 is to ensure the coordination, the strategic scientific and administrative management of PARC, including impact evaluation and the ethical issues management, in cooperation with the different governance bodies of the Partnership. The specific objectives of WP1 for year 3 are: - Task 1.1: Maintain an effective management and governance framework for the PARC consortium in compliance with the legal, ethical, financial and administrative rules and regulations and in compliance with the agreed timelines ensuring the highest quality standards; - Task 1.2: Manage the tools to ensure the Partnership’s progress and guide the PARC consortium and its activities in maintaining the course set out in the Grant Agreement, to achieve milestones and produce the agreed deliverables, within the defined budget and abiding by the highest quality standards; - Task 1.3: Maintain and update the monitoring framework for the Partnership; - Task 1.4: Ensure communication and collaboration between the Data and Ethics Protection Board (DEPB), notably composed of Ethics and Data contacts points from WP4, 5 and 7 and the PARC Consortium, and ensure that the PARC Participants follow the Ethics Charter in order to reduce and/or address ethical issues that may arise during the Partnership implementation. Description of work Task 1.1: Overall executive management and support of the Partnership Leader: ANSES (FR) Partners: All GSB members and WP co-leaders (as stated above) The activities of this task will be managed by the PARC Coordination Team (CT) composed of the PARC Coordinator, the Deputy-Coordinator and the ANSES Project managers. The PARC CT will ensure an efficient management of the PARC activities and associated administrative and budgetary issues. Management of the consortium and organisation of the Governance Bodies meetings: o Ensuring the respect and proper implementation of the “Terms of reference and rules of procedure” by the PARC Governing Board (GB) and of the Consortium Agreement (CA) by the PARC Grant Signatory Board (GSB) in compliance with the agreed timelines. o Setting the dates and organising the Partnership Consortium and Governance Bodies meetings (Mangement Board (MB), GB and GSB) to take place during the 3rd year of PARC: Consortium meetings: o A consortium meeting will be organised during the 3rd year of PARC on 13-16 May 2024 at the University for Health Sciences, Medical Informatics and Technology (UMIT) in Austria, according to the PARC Governance process timeline (D1.2). This meeting will offer the opportunity to share among the PARC participants what has been achieved, what are the difficulties encountered and how to solve them, what still needs to be done to progress towards achievement of the PARC objectives and what are the new topics PARC should address. DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 22 For the GSB: o A virtual meeting of the GSB will be organised beginning of summer 2024 in order to prepare the AWP of the year 4 and update the portfolio of projects and the PARC SRIA. o A virtual meeting of the GSB will be organised in December 2024 to discuss progress and approve the AWP for the year 4 and associated budget and annual summary report of the Y3 before submission to HaDEA. o Additional virtual GSB meeting(s) and/or written consultation(s) (through forms, poll, and emails) may be organised, if needed. For the GB: o A physical meeting of the GB will be organised back-to-back to the Consortium meeting in May 2024 to validate the strategy and get inputs from the GB for the preparation of the AWPY4. o A virtual meeting of the GB will be organised in November 2024. The objective will be to provide input and opinions on the PARC progression (AWPY4, SRIA) before submission to the HaDEA in December and discuss progress, indicators, sustainability, as well as the strategy for the AWPY5 that will be worked on by the MB and GSB over the spring/summer. o Additional virtual GB meeting(s) and/or written consultation(s) (through forms, poll, and emails) may be organised on other specific topics if needed. o Ahead of each GB meeting, the coordination team will prepare working documents with the GB co-chairs for each topic planned to be addressed during the meeting. These documents are tailored to fit with the GB level of understanding needed. For the MB: o Monthly MB meetings will be organised throughout the year, with two physical meetings, including one meeting in May 2024 back-to back to the Consortium meeting at the University for Health Sciences, Medical Informatics and Technology (UMIT) in Austria. The other MB meetings will take place online. Follow-up of the Partnership’s activities and budget: o Managing the information system (EMDESK) for the monitoring of the budget and help the financial administrators of the PARC institutions to ensure a proper and efficient use of the system. o Granting access rights to the PARC Consortium SharePoint to new individuals involved in PARC when requested in order to ensure that all individuals involved in PARC have access to internal working documents and calendar of meetings and actions to be done for the year 3 of PARC. o Assisting participants on specific administrative and financial issues. o Updating on request the Partnership handbook describing the internal requirements and specifying the common rules to be followed by all PARC Participants. Contractual documents generated by PARC activities: o Pursuing the preparation of contractual documents generated by PARC activities, when relevant: Intellectual Property Rights (IPR), Material Transfer Agreement and Data DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 23 Transfer Agreement; preparing, signing, and managing, when relevant, other PARC related agreements (e.g., confidentiality and collaboration agreements) that will arise during the 3nd year. o Establishing PARC collaboration agreements with external initiatives or organisations to support synergies o Ensuring the follow-up of the collaboration agreements signed with external initiatives or organisations, especially with JRC, though dedicated meetings. Communication: o Updating the internal and external communication rules of the Partnership handbook, in collaboration with WP3, when relevant. o Providing articles and news items to feed the PARC website in close collaboration with the WP3. o Providing rules and repositories to the PARC Participants for internal and external communication. Task 1.2: Scientific steering and implementation of Annual Work Plans Leader: ANSES (FR) Partners: All WP co-leaders, NHCPs, NHCs, The activities of this task will be managed by the PARC CT in close collaboration with the MB, GB, GSB, National Hub Coordinators (NHCs) and the Chemical Leaders and Methodology Leaders (CL/MLs). The MB will specifically play an active role to ensure the efficient setting up of the monitoring of the scientific progress and of the overall strategy of the Partnership, making sure that the PARC activities, resources and AWP are aligned. It will also ensure the relevance of the PARC work plan with regard to external events with WP3 (projects, initiatives, EU policies linked to the PARC objectives). Scientific steering : o Moderating the MB meetings and ensuring the cross-cutting scientific links between WPs o Assisting the PARC NHCs in coordinating the National Hub (NH) contributions and activities in PARC o Proposing amendments of the GA or solutions / redress actions to resolve any issues, and escalating unresolvable risks or issues to the relevant boards. o Aligning work programms to policy needs as defined by EU Agencies and partner countries. Synergies: o Ensuring the follow-up of opportunities for synergies (with WP3) (projects, initiatives, EU policies linked to the PARC objectives, National, EU and international initiatives …) Preparation and submission of AWPY4 with the Project Portfolio in Annex and ASRY3: o Coordinating the preparation, collection and submission to HaDEA of: DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 24 o The 4th AWP and updated PARC Project Portfolio in Annex, in December 2024. This will be done in close collaboration with the MB members, the Task co-leaders, the PARC Participants, the Task 2.1 partners, and in consultation with the relevant PARC governance bodies (see task 1.1 for the organisation of the Governance Bodies meetings). o The ASRY3 in December 2024. Preparation and submission of an updated PARC SRIA : o Coordinating the preparation and submission to HaDEA of an updated PARC SRIA validated by the GB at M33 Follow-up of deliverables, additional deliverables and milestones: o Ensuring respect of the different deadlines, and achievement of milestones, deliverables and additional deliverables according to the established review process. Task 1.3: Impact evaluation and Monitoring of the performance indicators of the Partnership Co-Leaders: DOMG (BE), INSA (PT) Partners: All WP co-leaders The monitoring frame and set of indicators will be further refined to ensure the key useful and impact-generating results and relevant target groups are clearly identified in order to maximise PARC’s impact and exploitation. The output indicators were presented at the GB of November 2023. Activities to be performed in the 3rd year include: o Presenting the first numbers on output indicators in the first PARC periodic report and feed these into the Biennal Monitoring Report. o Identifying potential barriers that could undermine the achievement of desired outcomes and impacts, and monitoring and discussing mitigation strategies. o Pursuing interaction with WP2 – task 2.3 on sustainability – for the development of surveys for sustainability indicators. o Developing further the outcome and impact indicators in collaboration with MB, GSB and GB, NHs and stakeholders. o In close collaboration with WP3, task 3.2, preparing easily interpretable indicator leaflets and communication elements on outcome and impact indicators that provide and communicate the link between the objectives, key results and (expected) impacts of PARC. o Presenting results of performance of output indicators to the MB/GB and disseminating these among WPs for awareness. o Continuing the discussions with the European Environment Agency to ensure input from PARC in, and synergies with, the Chemical Strategy for Sustainability (CSS) indicator framework being developed by the EC. Task 1.4: Ethics framework DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 31 The main goal of WP3 is to boost the impact of PARC outcomes through the diffusion of the knowledge produced within the Partnership while fostering synergies and collaborations with other projects/programmes at national, EU and international levels. The specific objectives of WP3 for year 3 are: - Task 3.1: Running the International Board (IB) and Stakeholder Forum (SF), and ensure their effective interaction with PARC’s projects, - Task 3.2: Continue the implementation of the communication strategy for PARC and promote its continuous improvement based on specific requirements from WPs, - Task 3.3: Continue establishing collaborations and synergies with identified relevant scientific/regulatory/policy initiatives at national, EU and international levels. Description of Programmed Activities Task 3.1: Building effective interactions Co-Leaders: EAA (AT): Stakeholder Forum; AUTH (EL): International Board Partners: ANSES (FR), EEA (EU), UBA (DE), IUSS (IT), LNS (LU), STAMI (NO), FMUL (PT), INSA (PT), APA (PT), NIB (SI), NKUA (EL), UOC (EL), GCSL (EL) Activity 3.1.1. Running of Stakeholder Forum (SF) In year 3 of PARC, the SF (established in year 1) will be continuing the work with the members of the SF. Together with two nominated SF chairs the strategy on information flow and inclusion of SF members’ perceptions according to the respective SF groups (NGOs, industry associations and other interest associations) will be discussed and further refined. Based on the discussions and outputs of the first two SF meetings and in close collaboration with SF co-chairs and WP coleaders, TLs and Project Mangers (PMs) topics of interest for the SF will be selected and prepared for presentation at the next SF meetings. A physical SF meeting early in Y3 will be held in Hall in Tyrol (AT) (organized back to back with the Consortium Meeting). Another online meeting will be organized in the second semester of Y3 to further present the work progress and to address the interests and needs of the SF members, raised in the latest meeting (all partners). Minutes of meetings will be taken to document progress and extracts will be published on the website. SF members will be encouraged to participate in existing PARC channels and communication tools (PARCopedia, SYNnet...), to offer them the possibility to articulate their needs and interact with the PARC consortium and other stakeholders. Partners involved: EAA, INSA, GCSL, UBA, STAMI, FMUL, APA, NIB, NKUA and UOC. Interactions with industry, in particular on the subjects of New Approach Methodologies (NAMs) and of SSbD under WP5 and WP8 respectively, will be promoted through the SF, which has representatives of industry associations and also with other relevant stakeholders through specific consultations and participation in dedicated meetings (AUTH, ANSES). Stakeholder interests brought to the attention of Task 3.1 will be taken up and forwarded to Tasks 3.3 and 2.2 or other WPs of specific interest. Activity 3.1.2. Running of the International Board (IB) TLs and partners will work in close collaboration to promote the interaction between the IB members and PARC WPs. Feedback on scientific steering needs will be collected from the WPLs DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 32 into a dedicated form that will be distributed in advance (two months prior the next IB meeting). The collected needs will be discussed and prioritized by the Activity 3.1.2 consortium, who will decide after consultation of the MB on the topics of the forthcoming IB meeting. Two meetings (one physical organized back to back with the Consortium Meeting in May 2024 and another online) will be organized to present the work progress and the main outcomes and to get feedback from the IB on the performance of Projects within PARC. Those meetings will also stimulate the interactions between PARC and external bodies (all partners). Partners involved: AUTH, UBA, IUSS, LNS, STAMI, FMUL, INSA, NKUA, UOC, GCSL. Task 3.2: Communication, dissemination, and awareness Co-Leaders: EEA (EU), NCPHP (HU) Partners: ANSES (FR), SpF (FR), EAA (AT), AGES (AT), UMIT (AT), VITO (BE), DOMG (BE), CIPH (CR), MOH-CY/SGL (CY), MU (CZ), HB (EE), TTL (FI), UBA (DE), BfR (DE), UI (IS), MOHIL (IL), ISS (IT), UNINA (IT), RSU (LV), NPHSL (LT), LNS (LU), RIVM (NL), NIPH (NO), STAMI (NO), NIOM (PL), FMUL (PT), INSA (PT), APA (PT), ENSP (PT), UAVR (PT), SZU (SK), JSI (SI), NIB (SI), NIC (SI), NIJZ (SI), ISCIII (ES), KEMI (SE), SLV (SE), FOPH (CH), UKHSA (UK), UOB (UK), AUTH (EL), EFET (EL), NKUA (EL), UOC (EL), BPI (EL), GCSL (EL) A3.2.1 Website and social media channels The PARC website and the social media channels (LinkedIn, Twitter/X, Facebook and Instagram accounts) will be maintained and updated regularly with new content including up to date information about upcoming events, progress updates, interviews and results by EEA, NCPHP, INSA, EFET, NKUA, NIJZ, BPI, and GCSL. A3.2.2 Development and implementation of the communication and dissemination strategy Following the developed communication and dissemination strategy, a continuous dialogue will be maintained with all WP co-leaders, WP3 contact points and National Hub contact points to translate the latest PARC results and the PARC agenda into communication and dissemination outputs, ensuring a coherent approach. The roadmap for the development of communication materials will be updated. New communication materials and activities, such as a PARC video and infographics on the projects’ outputs, will be created to increase PARC’s visibility, build and grow the PARC brand and engage stakeholders. The monthly Science Digest listing the latest peer-reviewed scientific PARC articles will continue to be produced, while the PARC Sampler bringing together all the latest news, interviews, science impact and much more will continue to be published twice a year. All public project deliverables produced under the project will be made available via the PARC website. Webinars, meetings and training activities for transfer of good practices, experience and knowledge will be organized in collaboration with WP9 partners. Partners involved: UMIT, EEA, NCPHP, LNS, STAMI, FMUL, INSA, APA, ENSP, UAVR, JSI, NIB, NIJZ, EFET, NKUA, UOC and GCSL. A3.2.3 Surveys and other tools to assess stakeholders' perception and concerns Outreach activities will be carried out to raise awareness of specific target groups. New focus groups will be organized to collect more in-depth information about citizens’ perceptions and DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 33 concerns about PARC-related subjects. The countries hosting focus group discussions will be selected in an internal call. The results of the first citizens’ survey will be analysed. All information gathered from the citizens’ survey and the focus groups will be fed into a deliverable on citizens’ perceptions and concerns. Stakeholder surveys will be carried out targeting the key stakeholder groups. Communication with the scientific community and with all stakeholders, including the general public, regulators and policy makers will be done in dialogue through the different communication channels (website, social media, newsletters, PARCopedia, workshops and other events) and with the involvement of the NHs. Partners involved: EEA, ENSP, FMUL, GCSL, INSA, NCPHP, NIB. A3.2.4 Risk communication A survey for mapping the risk perception of the different stakeholders on risk communication will be conducted in Greece and Slovenia by EFET and NIJZ for validation purposes. The results of the survey will be analysed and a report on the risk communication activities will be produced (as additional deliverable AD3.1). A.3.2.5 Monitoring of indicators Monitoring of indicators defined for the communication and dissemination activities will continue to feed into task 1.3 by DOMG, EEA, GCSL, INSA and NCPHP. Task 3.3: Networking and Synergies Co-Leaders: INSA (PT), NKUA (EL) Partners: ANSES (FR), MU (CZ), UBA (DE), FMUL (PT), APA (PT), ENSP (PT), UAVR (PT), JSI (SI), NIB (SI), NIC (SI), NIJZ (SI), EFET (EL), UOC (EL), BPI (EL), GCSL (EL) A3.3.1 Inventory of scientific activities relevant to PARC Update of the established database of partnerships, projects, networks and activities including platforms relevant to PARC within the frame of an efficient and dynamic collaboration strategy by filling up the online form created specifically for this purpose (all partners). A3.3.2 SYNnet and roadmap for promotion of synergies Continue updating SYNnet with the information gathered in the form created to register the established synergies and work on expanding the network to include new partnerships, projects, etc. and respond to PARC demands for synergies (ANSES, MU, UBA, FMUL, APA, ENSP, UAVR, JSI, NIB, NIC, NIJZ, EFET, UOC, BPI, GCSL). A3.3.3 Development of internal and external interaction strategies Revise and update the interaction strategy between SYNnet and WPs in order to identify and address internal needs and gaps (BPI, ENSP, NKUA, GCSL, INSA, UBA). Coordinate with WP/Task/Project leaders to create adequate incentives for external scientific activities that are relevant to PARC. SYNnet activities will be announced and published at the PARC website increasing the visibility of joint activities and of the external projects themselves. The first SYNnet Forum foreseen to DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 34 take place in Y2 will be organized in the beginning of Y3, back-to-back with a relevant scientific event, to promote dialogue and knowledge sharing among scientists (ENSP, FMUL, NIB, NIC, NIJZ, NKUA, UAVR, UOC, BPI). Deliverables: D3.5 1st Report on citizen's perception and concern: results of the surveys and focus groups – Leader: EEA (initial due date M28 postponed to M32) Additional Deliverables: AD3.1. Report on risk communication activities, Leader: EFET (M36) WP N° WP4 Lead Beneficiary UBA/SpF WP title Monitoring and exposure Part ner N° 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.9 1.10 1.11 1.12 1.13 2 3 3.4 3.6 3.9 4 4.1 4.3 4.4 4.5 4.6 4.7 5 5.2 6 7 8 8.1 8.2 8.4 10.1 Part ner shor t nam e ANSES INSERM INRAE CEA INERIS CNRS INRS ONIRIS OFB BRGM LNE CSTB EHESP SpF EAA MUI UG-AT UNIVE VITO KU Leuven UH PIH OVAM ISSeP UAntwerpen SCIENSANO EV-ILVO CIPH MOH-CY/SGL MU SZU-CZ VSCHT JU AU PM/ part ner 54.9 7.1 85.3 11.9 12.8 2.8 14.8 17.6 1.0 15.3 0.3 11.2 16.4 80.4 6.5 31.2 4.0 4.7 57.2 11.9 1.0 6.0 14,0 31.5 19.4 18.4 0.9 1.0 15.5 38.6 13.5 7.1 1.2 40.5 Partn er N° 10.3 10.4 11.2 13.1 14 14.1 14.3 15 15.1 15.2 15.6 16.1 18 19 20 20.2 20.5 20.6 20.7 21 21.1 22 23 24 24.3 25.1 25.2 25.5 25.6 Partn er short name REGIONH-RH UCPH UT SYKE TTL FFA UOULU UBA BfG UFZ KUM FraunhoferIBMT/IME UI MOH ISS CNR-IRSA UMIL UNINA UNIPD RSU UL NHPSL LSMU LNS UniLU KWR TNO UU-IRAS VUA PM/ partn er 10.0 12.3 12.0 6.1 27.0 4.5 1.5 70.7 13.5 57.6 7.3 12.7 9.0 4.5 13.3 13.6 7.0 1.8 2.0 31.3 4.7 0.3 6.7 65.8 21.0 3.2 0.5 2.6 13.5 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 35 Partn er N° 25.7 25.9 26 26.2 26.3 26.5 26.7 27 27.2 27.3 29 29.3 30 31 31.4 32 32.2 32.3 33 33.4 33.3 34 34.1 34.2 34.5 34.6 34.7 34.8 35.3 Partn er short name WR SRU NIPH STAMI NILU NMBU UNN NIOM UG-PL WULSSGGW INSA ENSP SZU-SK JSI ULFFA NIJZ NLZOH ARSO CSIC ULPGC UGR ISCIII EASP FISABIO IISPV INNST UCLM UPV-EHU ULUND PM/ partn er 14.0 9.5 34.9 9.5 5.5 0.5 0.3 35.3 5.6 14.2 33.2 2.2 9.00 48.6 6.8 10.2 0.2 2.1 32.7 0.4 24.8 38.0 6.5 1.0 2.5 4.0 6.5 8.5 4.4 Partner N° 35.4 35.6 35.8 35.10 36 36.1 36.2 36.3 37 38 40 41 45 47 50 53 54 55 56 57 58 Partner short name ORU SU IVL SLU AUTH EFET GCSL NKUA BPI FOPH UNISANTE EAWAG USI SECO UKHSA UKCEH EA HSE IOM UBAH UINABDN PM/ partner 11.9 8.5 11.4 17.0 16.0 1.9 1.0 35.5 15.0 1.0 6.3 26.5 6.2 0.4 3.5 5.0 1.5 5.0 1.1 3.0 0.5 Start M25 End M36 Objectives The main goal of WP4 is to monitor chemicals guided by clearly defined regulatory and policy challenges both in humans and in the environment, observing different sources, chemical fates and exposure pathways, international activities, and coordinate with the WHO EHP on Human Biomonitoring (HBM) launched in Budapest in July 2023. The specific objectives of WP4 for year 3 are:  Task 4.1: Continuation of an EU-wide general population HBM survey, continuing occupational surveys in health care sector and waste sector, developing targeted surveys (design and supporting materials), preparing and implementation of following aspects in above mentioned surveys: effect biomarkers, innovative (sampling) techniques for HBM in a tiered approach starting with state of the art analyses, update and integration of QA/QC aspects and analyses plan in the HBM surveys, evaluation of new chemical analysis methods needs, derivation of HBM guidance values (HBM-GV).  Task 4.2: Complete the development of a mechanism to define priority chemicals/matrices/endpoints for environmental monitoring studies. Complete a first monitoring study on PFAS and endocrine disrupting chemicals (EDCs) and evaluate the process with regard to future monitoring studies. Initiate a study on human exposure to organic chemicals from environmental non-food sources.  Task 4.3: Novel methodologies will be developed in a tiered approach for improvement and renewal of current monitoring approaches, with a focus on early life stages and on early warning systems for the timely observation of the occurrence of chemicals of emerging concern in the environment-food-human continuum. The work will be covered in 4 ongoing projects (started in year 1) and 3 projects started in year 2 and 1 project starting in year 3 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 36 From year 3 a specific attention will be given to transversal activities inside WP4 to ensure that the different tasks align their activities in the perspective of a better integration of human and environmental monitoring networks. Specifically, the project 4.2.c will be a collaboration between T4.1 and T4.2, with strong links to T4.3. In particular, a list of priority substances will be defined early in Y3 that link human and environmental monitoring. Case studies for joint data evaluation will be defined to evaluate the benefits and limitations of an integrative assessment of human and environmental exposure to chemicals. Description of Programmed Activities Task 4.1: Human Biomonitoring Co-Leaders: VITO (BE), ISCIII (ES) Partners: ANSES (FR), AU (DK), AUTH (EL), BPI (EL), CEA (FR), CSIC (ES), EAA (AT), EHESP (FR), FFA (FI), TTL (FI), FISABIO (ES), FOPH (CH), HSE (UK), KI (SE), IMROH (HR), INRAE (FR), INRS (FR), INSA (PT), INSERM (FR), INSST (ES), IOM (UK), KUM (DE), ISS (IT), ISSeP (BE), IVL (SE), JSI (SI), KU Leuven (BE), LNS (LU), LSMU (LT), MOH-CY/SGL (CY), MOH (IL), MU (CZ), MUI (AT), MUW (AT), NIJZ (SI), NIOM (PL), NIPH (NO), NLZOH (SI), NPHSL (LT), ONIRIS (FR), UKHSA (UK), PIH (BE), REGIONH-RH (DK), RSU (LV), SRU (NL), SCIENSANO (BE), SLU (SE), SpF (FR), STAMI (NO), SZU-CZ (CZ), SZU-SK (SK), THL (FI), UAntwerpen (BE), UBA (DE), UGent (BE), UGR (ES), UH (BE), ULFFA (SI), ULPGC (ES), ULUND (SE), UMU (SE),UMIL (IT), UNINA (IT), UNIPD (IT), UNISANTE (CH), UNIVIE (AT), UNN (NO), UOULU (FI), UOC (EL), UPV/EHU (ES), USI (CH), UU-IRAS (NL), WULS-SGGW (PL), CIPH (HR), SHSO (CY), SDU (DK), Fraunhofer-IBMT (DE), UFZ (DE), NCPHP (HU), UI (IS), VSCHT (CZ), EASP (ES), SECO (CH) A4.1.1 Design, alignment and fieldwork of HBM studies The implementation of a general population HBM survey is ongoing and will be further supported (linked to P4.1.1.2.a_Y1_GenHBMSurvey_VITO). Proposals for add-ons to be implemented, as small-scale research components, in the general survey will be finalized. The add-on topics are: i) implementation of effect biomarkers (linked to P4.1.3.3.a_Y1_RoadmapLinkingHBMhealth_SpF_VITO), ii) identify the contribution of specific environmental compartments, products to internal exposure levels (in collaboration with T4.2 - in project P4.2.c_Y3_HumanExposure_INERIS_AU), and (iii) apply innovative screening methods (Suspect screening (SS), Non targeted screening (NTS)) (in collaboration with T4.3 - in project P4.3.2.c_Y3_H03 Complementary developments_JSI/UAntwerpen). Project proposals for targeted surveys will be developed and submitted in Y3 to be initiated in Y4 (ISCIII, LNS, SpF, UBA, VITO). Preliminary priorities for targeted studies include: dietary exposure to e.g., food related exposures in young children, prenatal and newborn exposure to e.g., endocrine disruptors and Persistent Organic pollutants (POPs), health effects and risk factors related to (accumulated) exposure in the middle-aged population (40-69y) and elderly (70-85y), time trends in repeatedly sampled cohorts/regions and/or biobanked samples from longer time periods, PFAS hotspots. During the first year, two occupational surveys focusing on the waste management sector (linked to P4.1.1.4.d_Y1_OccupWaste_ENSP_TTL) (phthalates, metals, flame retardants, bisphenols) and the health care sector (linked to DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 37 P4.1.1.4.c_Y1_Occuphealthcare_TTL_SRU) (HMPs and disinfectants) (HSE, INRS, INSST, IOM, MU, RSU, SRU, TTL, UGR) have been designed. Standard Operating Procedures (SOPs) are performed for harmonised sampling procedures in accordance with the procedures for the PARC Aligned Studies and ethical permissions are applied in each participating countries in the end of Y1 and Y2. Sampling related to these studies will continue in Y3 for the waste management sector (AU, INSA, ENSP, ISS, KUL, LNS, MOH-CY/SGL, NIOM, STAMI, UMIL, UNIPD, UNINA, UNISANTE, WULS-SGGW, ULUND, IPA) and the health care sector (HSE, INRS, INSST, IOM, MU, RSU, SRU, TTL, UGR, LNS). Samplings will include also samples collected according to harmonised and quality assured SOPs for effect marker analyses (which have been planned in collaboration with P4.1.3.3a) and applying new innovative methods (T4.3: linked to P4.3.2.b_Y2_H02). The project P4.1.1.4.a_Y1_OccupFeasability_TTL will be extended into Y3 to prepare a final report and scientific publication. S4.1.1.1-supporting materials for a harmonized HBM conduct: the Y3 work plan will focus on the update of the material transfer agreement developed under HBM4EU and the elaboration of effective communication materials for reporting the research results to participants (CIPH, CSIC, EAA, EASP, FOPH, Fraunhofer-IBMT, IMROH, INSA, ISCIII, ISS, ISSeP, JSI, LNS, LSMU, MOH-IL, MUW, NIJZ, NIOM, PIH, RSU, SpF, STAMI, THL, UBA, UGR, ULUND, UMU, UOULU, UPV). Details per project: - P4.1.1.2.a_Y1_GenHBMSurvey_VITO: Partners that will contribute to the PARC Aligned Studies in children (6-11 years) are UKHSA, RegionH-RH, RSU, UT, HB, WULS-SGGW, SZUCZ, NCPHP, ISCIII, INSA, AUTH, JSI, MOH-CY/SGL, UBA, SPF, EAA, LNS. Partners that will contribute in teenagers (12-17 years) are UKHSA, RegionH-RH, NIPH, ULUND, RSU, NIOM, JSI, AUTH, INSA, UBA, SPF, VITO/PIH, and partners that will contribute in adults (18-39 years) are UKHSA, LSMU, RSU, UT, HB, UI, NIPH, SZU-CZ, NIOM, NCPHP, EASP, UPV, AUTH, INSA, MOH-CY/SGL, ISS, UBA, SPF, ISSeP, LNS, MOH-IL, RIVM. Discussions on potential contribution from Ireland and Slovakia are ongoing. Substance groups prioritized for analysis are in children: Phthalates and substitute DINCH, Bisphenols, Pesticides, metals in urine, Mercury (hair), in teenagers: PFAS, Phthalates and substitute DINCH, Bisphenols, arsenic species, pesticides, in adults: PFAS, metals in urine/blood, pesticides, bisphenols. In all age groups cotinine, creatinine and specific gravity will be assessed. Sample collection activities (up to 3650 children, 2750 adolescents and 4900 adults) continue throughout Y3, overall coordination will be taken up by VITO supported by ISCIII, UBA, SPF, LNS, INSA, RegionH-RH. A subset of the PARC Aligned Studies will contribute to the add-on “effect biomarker implementation”. Following partners with HBM studies in children will implement effect biomarkers: WULS, AUTH, ISCIII, LNS, JSI, NPHC, RSU, MOH-CY/SGL. Following partners with HBM studies in teenagers will implement effect biomarkers: AUTH, JSI, RSU, NIPH, VITO/PIH, SPF, NIOM. Following partners with HBM studies in adults will implement effect biomarkers: AUTH, LNS, NPHC, RSU, MOH-CY/SGL, NIPH, SPF, NIOM, EASP, ISSeP. DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 38 - P4.1.1.4.a_Y1_OccupFeasability_TTL: learnings from this project can potentially be considered in sentinel surveillance study (P4.1.1.4.b_Y1_SentinelSystem_KULeuven) conducted as part of PARC. Due to delay in data exchange the project will be extended into Y3 to prepare the final report and scientific publication. Scientific publication is drafted (TTL (FI) SpF (FR), INRS (FR), INSA (PT), LSMU (LT)). - P4.1.1.4.b_Y1_SentinelSystem_KULeuven: The sentinel project has been reoriented to focus on occupational population rather than general population. The focus of the project is on the Assessment of exposure to substances of high concern in the working population through a sentinel surveillance system, to establish a robust sentinel surveillance system in occupational settings. Phase 1 in Year 3: An Updated Mapping Exercise (Go/No-Go Decision): This phase incorporates a detailed mapping exercise in collaboration with partner countries, intending to implement the sentinel surveillance system at the national level. The exercise involves considerations for occupational sectors to be included and substances and compounds to be analyzed for assessing exposure to substances of high concern in each partner country. The mapping exercise encompasses key scientific components: Capacity Assessment:  Identification of occupational sectors and socio-economic status.  Identification of prevalent occupational diseases, emerging health risks, and patterns of morbidity and mortality in the working population.  Evaluation of existing infrastructure, resources, and technical capabilities within each partner country for implementing a sentinel surveillance system.  Engagement assessment of physicians/nurses, employers, and workers, including the determination of the number of occupational physicians that can be recruited.  Assessment of the availability of trained personnel, laboratory facilities, and information systems for data collection and analysis.  Identification of the most relevant compounds and substances (along with relevant biomarkers) in the targeted and selected occupational sector, with partner countries making choices.  Determination of laboratories available for each type of exposure biomarker to measure each selected substance of high concern. Legal and Ethical Considerations:  Review and analysis of legal and ethical frameworks governing data collection, storage, biobank procedures, ethical committee application processes and durations, and dissemination in occupational health surveillance.  Development of protocols to ensure compliance with international standards and guidelines. Pilot Implementation Plan:  Development of a pilot implementation plan based on the findings of the mapping exercise.  Design of protocols for testing the efficacy and scalability of the sentinel surveillance system in a targeted working population. Upon completion of Phase 1 in Year 3, the project anticipates achieving a comprehensive understanding of the readiness and capacity of partner countries for implementing a sentinel surveillance system in occupational settings. These outcomes will inform the development of DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 39 tailored interventions and protocols for the subsequent project phase, thereby contributing to the global enhancement of occupational health monitoring - P4.1.1.4.c_Y1_HealthCareSurvey_TTL_SRU: In the end of year 2 and beginning of year 3, hospitals and volunteering participants will be recruited. Field workers have been trained to collect environmental and biological samples and contextual data according to harmonised methods and quality assured SOPs during year 2. Next, the sampling campaign will be launched, which will start early 2024 and continue in Y3. Collected samples will be shipped to laboratories for analysis. Aim is to include 20 hospitals and up to 650 workers. Analysis of samples is planned to begin in Y3. Chemical substance groups prioritized for analysis are cytotoxics, anesthetic substances and disinfectants. Effect Biomarkers prioritized for analysis are markers for genotoxicity, oxidative stress and inflammation. Samples are collected from hospital settings in 10 countries by the following partners: TTL (FI), SRU (NL), MU (CZ), UGR (ES), INRS (FR), ISS (IT), UMIL (IT), UNINA (IT), UNIPD (IT), RSU (LV), LNS (LU), ENSP (PT), HSE (UK), IOM (UK), INSST (ES). This activity is led by SRU and TTL and made in collaboration with task 4.1.2. The project specific data management plan is finalised by SRU and TTL by the beginning of Y3 with the support from the other partners (see the list above) and T7.1. - P4.1.1.4.d_Y1_OccupWaste_ENSP_TTL: Year 2 has been devoted to the preparation of SOPs for harmonised samplings, information materials and submission of the study protocol to the Ethical Committees. Data Management Plan (DMP) has been prepared in collaboration with WP7, as well as the online training on the implementation of the study protocols and procedures (collaboration with WP9). Sampling campaigns will begin by the end of Y2 and continue in Y3 of PARC. Aim is to cover 40-50 companies and up to 700 workers. Analysis of samples is planned to begin in Y3. Chemical substance groups prioritized for analysis are metals, Flame retardants, Phthalates, Bisphenols, PFAS, plasticizers. Effect Biomarkers prioritized for analysis are markers for genotoxicity, oxidative stress and inflammatory markers. Samples are collected in 13 countries by: ENSP-UNL (PT), AU (DK), ISS(IT), UNIPD (IT), UMIL (IT), UNINA (IT), WULS (PL), ULUND (SE), STAMI (NO), AUTH (GR), INSA (PT), TTL (FI), LNS (LU), MOH-CY ( CY), NIOM (PL), IOM (UK), HSE (UK) and UGR (ES). A4.1.2 Laboratory analysis and quality assurance No project for this activity since it is a transversal activity. During Y3, the selection of the best, state-of-the-art exposure biomarkers and analytical methods will be done (AU, AUTH, BPI, CEA, EHESP, FFA, FISABIO, IMROH, INSA, ISCIII, ISS, JSI, KU Leuven, KUM, LNS, LSMU, NIOM, NIPH, NPHSL, UKHSA, RSU, SRU, SpF, STAMI, SZU-SK, THL, UAntwerpen, UGR, ULFFA, ULPGC, ULUND, UMIL, UNN, UOC, UOULU, USI, VSCHT) according to the needs identified in the proposals that will be developed during Y3 for the targeted studies to be implemented from Y4. For occupational studies, selection of exposure and effect biomarkers have been made already during Y2 of PARC. Substance groups prioritized for analysis in P4.1.1.4.c_Y1_Occuphealthcare_TTL_SRU include hazardous medicinal products including cytotoxic drugs and anaesthetic gases, alcohols used in disinfection and cleaning products. Effect markers prioritized include genotoxicity, inflammatory and oxidative stress markers. Substance groups prioritized for analysis in P4.1.1.4.d_Y1_OccupWaste_ENSP_TTL: Metals, DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 40 Flame retardants, Phthalates, Bisphenols, PFAS, plasticizers. Effect markers prioritized include genotoxicity, inflammatory and oxidative stress markers. Candidate laboratories (13 for waste management and 15 for health care study) for the analysis of different exposure and effect markers have been also selected. During Y2 and beginning of Y3, these candidate laboratories are expected to ensure their quality. For those biomarkers for which no proficiency test is provided by PARC-QEQUAS, an internal small-scale QA system/inter-laboratory comparison will be organised. Analysis of some samples is expected to start Y3. This applies especially to some effect biomarkers (like PBL MN) which require processing soon after the collection of samples. The Quality Assurance Working Group (QAWG) (AU, ISCIII, NIPH, UAntwerpen, and WR) and collaborating partners (LNS) will still work in close collaboration with T9.1 and T9.3 to ensure the quality and comparability of the HBM data generated under T4.1. It is expected that the PARCGEQUAS QA/QC program will begin in the spring of 2024 (Year 3 of PARC). In parallel, the proficiency test for total mercury in hair will be also implemented in Y3. This program is organised, implemented and coordinated by ISCIII with input from T9.3. Based on the timeline for the HBM surveys currently planned, the QA/QC program is expected to run for at least two more years (2025-2026 and 2026-2027) to cover the needs of all the studies. In Y3 we expect to have the first list of qualified laboratories that can analyse HBM samples in PARC. In addition, QA/QC aspects related to the innovative sampling techniques will be evaluated and included in the design of the add ons for the HBM surveys (ISCIII, LNS, MU, ONIRIS, UAntwerpen, UGR, UNIVIE, and UOC). The working group on reference analytical methods (ISCIII, ISS, IVL, LNS, MUI, NIPH, SCIENSANO, UAntwerpen, ULUND, UNIVIE, and UOC) will continue working in the inventory concept to identify strong/weak points related to the analytical methods for the selected substances. This information will allow to identify knowledge gaps and the concrete needs for analytical methods development. In addition, the need to harmonise important preanalytical issues will be also covered in this inventory. This activity will lead to the preparation of a project proposal on method development (or improvement). In Y3 the chemical analysis plan (adapted templates, monitoring tool on the sharepoint…) will be approved and implemented (LNS, MU, NIOM, RSU, SRU, SCIENSANO, SpF, THL, TTL, UAntwerpen, UBA, UGR, and ULUND). The harmonisation, quality assurance and implementation of effect biomarkers will take place under P4.1.3.3.a_Y1_RoadmapLinkingHBMhealth_SpF_VITO, and details are provided below. A4.1.3 Link exposure and health related information No transversal activities under A4.1.3, all captured in projects. Details per project: - P4.1.3.1.a_Y1_Derivation of HBM-GVs_UBA: Year 3: Health-Based HBM Guidance Values (HBM-GVs) will be derived for a third set of prioritised substances (ANSES, AUTH, MOH-IL, NIJZ, NIPH-FHI, TTL, UBA, Unisante, SECO, LNS). HBM-GVs for selected substances or their specific exposure biomarkers will be derived according to the strategy agreed under HBM4EU and described by Apel et al. (2020; https://doi.org/10.1016/j.ijheh.2020.113622). In principle, all lead experts conduct a literature search on the substance under consideration to determine the current state of toxicological/epidemiological knowledge. Depending on the data basis, the experts decide whether epidemiological data, or else a recognized external toxicity reference value respectively occupational exposure limit, or a point of departure from an experimental study DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 47 the performances of selected innovative sampling (silicone wristbands, dried blood spots) and exposure measurement (HRMS based SS/NTS) related methods, in comparison with those of conventional and targeted approaches. Another goal is to evidence new exposure markers associated to the considered occupational exposures. During Y3, sample collection will be completed and a first round of sample analyses will be performed, based on the SOPs elaborated on Y2. In close connexion with the previous project 4.3.2.a, an interlab assay will be designed and realized as a major piece of method performance assessment and harmonization. This workplan will involve the whole set of partners embedded in the project based on complementary capacities (then contributions) that have been identified on Y2 in term of targeted versus SS measurements and type of samples analyzed.[Lead: INRS (FR), LNS (LU), participants: WULSSGGW (PL), INRAE (FR), MUI (AT), UGR (ES), STAMI (NO), TNO (NL), UAntwerpen (BE), TTL (CZ), MU (CZ), JSI (SI), WR (NL), BPI (GR), AUTH (GR), AEF (FI)]. - P4.3.2.c_Y3_H03-Complementary developments_JSI/UAntwerpen. This new project will elaborate and conduct a set of actions complementary to those already running in the previous project H01 and H02 that cannot address all necessary aspects of innovative method assessment and improvement with regard to their application to human samples. One primary project objective is to evaluate the effectiveness of complementary methodological strategies including orthogonal liquid chromatography separation systems (e.g. HILIC adapted to highly polar compounds/metabolites), alternative sample preparation protocols directly impacting the analytical results (e.g. deconjugation, phospholipid removal), and the use of alternative noninvasive matrices (e.g. hair or saliva), finally leading to potential additional SOPs of interest. A second objective is to start capitalizing on main results and lessons learnt originated from our transversal projects related in particular to QA/QC and data processing issues, as a means to apply those gained outputs to new batches of real samples as an extended illustration of their usefulness. To that end, a direct link will be established to PARC task 4.1 aligned studies to source a set of supporting samples already planned to be analysed through conventional targeted methods for complementing these analyses with innovative screening results. During Y3, the defined workplan includes more specifically the following actions: consolidation of the refined global roadmap and its mutual understanding by all partners, comprehensive synthesis of existing knowledge regarding innovative methodological approaches, encompassing sampling (hair and saliva), sample preparation (deconjugation, phospholipid removal), and instrumental analysis (HILIC chromatography), summarizing known advantages and limitations of those innovative approaches in the specific light of policy priorities within the overarching objectives of PARC's science-to-policy goals. [Lead: JSI (SI), UAntwerpen (BE), Participants: AUTH (GR), BPI (GR), CEA (FR), IISPV (ES), ISCIII (ES), ISS (IT), LNS (LU), MU (CZ), MUI (AT), SU (SE), UFZ (DE), VITO (BE), VSCHT (CZ), VUA (NL), WR (NL), WULS (PL), INRAE (FR), CNRS (FR), CSIC (ES), INRS (FR), AU (DK)]. A4.3.3 Environment samples based proof-of-concepts Details per project: - P4.3.3.a_Y1_E01_Wastewater based epidemiology_UFZ-UBATH. This project addresses both human and environmental exposure, focusing on fingerprinting of wastewater treatment plant influents as a proxy for community wide human exposure assessment and on screening of wastewater treatment plants (WWTP) effluents to assess the release of Chemicals of Emerging DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 48 Concern (CECs) into the water cycle. In year 3, we will focus on the delivery of a pan-European study to capture both human and environmental exposures to hazardous chemicals. This will include further development targeted and screening methods including validation for the assessment of human exposure will be continued Partners involved: UFZ (DE), UBATH (UK), MUI (AT), UCPH (DK), EAWAG (CH), KWR (NL), UniLU (LU), INERIS (FR), BfG (DE), BRGM (FR), IRFM (IT), ORU-MTM (SE), SLU (SE), UAntwerpen (BE), JSI (SI), WULS-SGGW (PL), JU (CZ), UG-PL (PL). For the environmental exposure assessment, the prioritization of features and patterns from screening data and the method development for new enrichment tools will be finalised [Partners involved: UFZ (DE), UBATH (UK), MUI (AT), UCPH (DK), EAWAG (CH), ORU-MTM (SE), SLU (SE), JSI (SI), KWR (NL), UniLU (LU), VUA (NL), INERIS (FR), BfG (DE), VITO (BE), BRGM (FR), WULS-SGGW (PL), JU (CZ), MU (CZ), INRAE (FR), OFB (FR), UL (LV), UG-PL (PL).]. The Method for high-throughput EDA [Partners involved: UFZ (DE), UCPH (DK), EAWAG (CH), ORUMTM (SE), SLU (SE), KWR (NL), VUA (NL), ISS (IT), INERIS (FR), BfG (DE), VITO (BE), ULFFA (SI), JU (CZ), INRAE (FR), UG-PL (PL)] and the data mining methods and proof of concept on existing datasets [Partners involved: UFZ (DE), UBATH (UK), MUI (AT), UCPH (DK), EAWAG (CH), KWR (NL), UniLU (LU), INERIS (FR), BfG (DE), BRGM (FR)] will be developed. WBEbased human exposure to chemicals will be assessed acrossed Europe via the development of Wastewater Based Epidemiology (WBE) workflows and their application in samples collected across European towns and cities. - P4.3.3.b_Y2_E02-Sentinel animals_ONIRIS. This project will elaborate and conduct a proof-ofconcept demonstrating the potential use of sentinel animal species for capturing human exposure to emerging chemicals along the food chain. During Y3, the selection of relevant marine and terrestrial animal species such as mussels, earthworm or bird eggs to be considered in the project will be fixed based on concerted discussions performed on Y2. The envisaged operational workplan as refined on Y2 will be conducted associating the complementarities of the different partners involved. The identification of a first set of relevant and accessible archived samples and data to be used in the project will be completed, as well as the necessary Material Transfer Agreement (MTA) elaboration, sample shipment, and data sharing from sample owners to receivers. The perspective of developing this project in a support to policy context (e.g., contribution to early warning system through the capture of chemical hazards of concern for ecosystem and human health will be pursued. [Lead : ONIRIS (FR), Participants : ANSES (FR), AU (DK), BfR (DE), Eawag (CH), CSIC (ES), INRAE (FR), JSI (SI), JU (CZ), OFB (FR), ORUMTM (SE), SU (SE), UFZ (DE), UG-AT (AT), VUA (NL).]. A4.3.4 Food samples based proof-of-concepts - P4.3.4.a_Y2_F02Food items exposure_ANSES. This project will elaborate and conduct a set of complementary studies to illustrate the facility of innovative screening approaches (SS/NTS/EDA) to investigate real life complex co-exposures and emerging chemicals from food items. During Y3, the selection of relevant food items to be considered in the project will be fixed based on concerted discussions performed on Y2. The envisaged operational workplan as refined on Y2 will be conducted associating the complementarities of the different partners involved. The identification of a first set of relevant and accessible archived samples and data to DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 49 be used in the project will be completed, as well as the necessary MTA elaboration, sample shipment, and data sharing from sample owners to receivers. The perspective of developing this project in a support to policy context (e.g. contribution to early warning system through the capture of chemical hazards of concern associated to food exposure) will be pursued. [Lead: ANSES (FR). Participants: INRAE (FR), VUA (NL), BfG (DE), CEA (FR), CNRS (FR), EAWAG (CH), CSIC (SP), ISS (IT), JSI (SI), MUI (AT), Oniris (FR), SLU (SE), UAntwerpen (BE), UL-FFA (SL), VSCHT (CZ), WR (NL), WULS (PL), EV-ILVO (BEL), GCSL (GR).] Deliverables: D4.2. 1st Proof-of-concept assessing the usefulness of innovative (self-) sampling combined with integrated suspect/NTS/EDA approaches (P4.3.3.a_Y1_EO1-Wastewater based epidemiology_UFZ-UBATH, delayed from M36 to M48), Leader: VUA (M35). New delivery date M48 D4.3 1st Progress report on the general survey (P4.1.3.3.a_Y1_RoadmapLinkingHBMhealth_SpF_VITO, M52 and P4.1.1.2.a_Y1_GenHBMSurvey_VITO, M81) – Leader: VITO (M36) D4.4 Progress report on ongoing monitoring projects (P4.2.a_Y1_ENVEnvironmentalPilotSurvey_INERIS_AU, M36) – Leader: AU (M36) Additional Deliverables AD4.2 Periodic report on analytical methods and measurements for exposure and effect biomarkers (P4.1.3.3.a_Y1_RoadmapLinkingHBMhealth_SpF_VITO, M52) – Leader ISCIII (new delivery date M36) AD4.3 Derivation of HBM-GVs – first set (P4.1.3.1.a_Y1_DerivationofHBM-GVs_UBA, M36) – Leader UBA (new delivery date M36) AD4.8. Report on the occupational exposure in general population surveys: analysis of existing data and recommendations for future general population studies (P4.1.1.4.a_Y1_OccupFeasability_TTL, M29) – Leader TTL (new delivery date M29) AD4.9 Final report on the prioritization project (P4.2.b_Y2_MonitoringFrame_AU_INERIS, M30) – Leader: AU/INERIS (M34) AD4.10 Description of the study concept (P4.2.c_Y3_HumanExposure_INERIS_AU, M72) – Leader: INERIS/AU (M36) AD4.11 Progress report statistical analyses (P4.1.4.2.a_Y1_DataAnalysisHBM4EU_VITO, M36) - Leader: VITO (M36) WP N° WP5 Lead Beneficiary ANSES/BfR WP titl e Hazard Assessment Par tne r N° 1 1.1 1.2 1.4 1.5 1.6 1.8 3.2 3.4 3.7 3.9 4.1 4.7 5 5.1 5.3 8 10.1 10.2 10.5 14 15.1 15.2 16 16.1 16.2 16.3 16.4 16.6 16.7 16.8 16.9 16.10 17 20 20.3 20.5 24.1 24.2 25 25.4 25.5 25.6 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 50 Par tne r sh ort na me ANSES INSERM INRAE INERIS CNRS INRS IRSN AIT MUI UIBK UNIVE KU Leuven UAntwerpen SCIENSANO UGent VUB MU AU DTU SDU TTL BfG UFZ BfR Fraunhofer KIT IUF IfADo RPTU TUB UKON TiHo UHC NCPHP ISS IRFM UMIL LIH LIST RIVM UL-LACDR UU-IRAS VUA PM / par tne r 75.2 197.4 70.4 8.4 23 12.6 2 12 21.6 14.9 39.3 10 32.2 33.3 14.2 22 11.5 11 44.5 34.4 1.9 9.5 59.1 122.9 13.9 11.6 48 12 12 0.6 7 6.8 9.8 27.7 26 10.3 9 27.6 4 16.4 46.7 24 8 Partn er num ber 25.7 25.8 26 26.1 26.2 26.3 26.4 26.5 26.6 27.1 27.2 29 29.5 31 31.2 31.3 31.4 31.5 33 33.2 33.4 34 34.5 35.2 35.6 35.10 35.12 36 37 41 54 58 59 Partn er short nam e WR WU-TOX NIPH IMR STAMI NILU NIVA NMBU NVI IEP-NRI UG-PL INSA UAVR JSI NIB NIC ULFFA MFUM CSIC UNAV UPO ISCIII IISPV KI SU SLU UU AUTH BPI EAWAG EA UINABDN UOB PM/ partn er 9.6 5.2 56.5 7.5 15 6.5 14.2 13 12 10.7 18.6 40.2 6.5 7 33.5 37.5 12 0.3 77 28.5 12 44.5 43 1 6.5 34 16 21 46.1 23 0.5 0.2 18 Start M25 End M36 Objectives The main goal of WP5 is to focus on Hazard Assessment (HA) for human and environmental health on three different directions: fill data gaps (task 5.1), develop and/or improve methodologies for HA to progress towards NGRA (task 5.2) and to work on Adverse Outcome Pathways (AOPs), quantitative systems toxicology and physiologically based toxicokinetic (PBTK) modelling (task 5.3). The specific objectives of WP5 for year 3 are: - Task 5.1: Collection of data is the core aspect of the work in Y3, for human health (prioritised compounds are Bisphenol A (BPA) alternatives/analogues and alternaria toxins and enniatins) and the environmental health (prioritised compounds are BPA alternatives, including mixtures, cyanotoxins and mycotoxins). - Task 5.2: The focus of our work will be on advancing and refining innovative methodologies for hazard identification. In human health, we will continue focusing on five different endpoints and effects: immunotoxicity, non-genotoxic carcinogenicity, (developmental) neurotoxicity, endocrine disruption (with a focus on thyroid) and metabolic disruption. In environment, we will be creating New approach methodologies (NAMs) in four primary areas employing i) in silico and modelling tools, ii) invertebrate animal models, iii) vertebrate models, and newly iv) complex microbial community. - Task 5.3: The objectives for Y3 are to keep fostering the different core or extended groups DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 51 established in Y1 and Y2 that are relevant for the activity of this task: omics, AOPs, bioinformatics, effect markers, PBTK, and in vivo/in vitro mode of action. We will use and update when needed our inventory and mapping established in Y1 and Y2 of available knowledge, reference in vivo/human datasets, activities and models in systems biology, PBTK and AOP frameworks and prioritising additional studies. We will also continue the studies initiated in Y1 and Y2 to characterise coregulated gene networks, for already published AOPs (to make them quantitative) and linking chemicals to available AOPs, linking omics data to human physiopathology, generating high quality data. Description of Programmed Activities Task 5.1: Toxicity testing addressing data gaps of concern Co-leaders A5.1.1: NIPH (NO), INSA (PT), Co-leader A5.1.2: BPI (EL) Participants: Activity 5.1.1: ANSES (FR), BfR (DE), BPI (EL), CNRS (FR), Fraunhofer-IBMT (DE), IMR (NO), INRAE (FR), INRS (FR), INSA (PT), INSERM (FR), ISCIII (ES), ISS (IT), LIH (LU), MUI (AT), NIB (SI), NILU (NO), NIPH (NO), NVI (NO), Sciensano (BE), SDU (DK), STAMI (NO), TTL (FI), TUB (DE), ULFFA (SI), UMIL (IT), UNAV (ES), UNIVIE (AT), WU-TOX (NL) Activity 5.1.2: BPI (EL), EAWAG (CH), IEP-NRI (PL), IISPV (ES), INERIS (FR), INRAE (FR), NIB (SI) NIVA (NO), SDU (DK), SLU (SE), SU (SE), UAVR (PT), UFZ (DE), UG-PL (PL), UGent (BE), UU (SE), Cefas-Defra (UK), UOB (UK). A5.1.1 Closing data gaps of concern for human health. We look forward to continuing the lab-based activities in year 3 and to having time to discuss and interpret the results and disseminate our findings to regulatory EU and national agencies (e.g EFSA, ECHA, EMA) to ensure regulatory uptake of the results. Results will also be shared with some institutions which showed interests in these activities (Health Canada, Ontario University and RIVM). For year 3 is planned the publication of the results in peer-reviewed journals, presentation of data in conferences, meetings (e.g. SETAC, WP5 annual on site meeting), and the preparation of new projects. In Year 3 the project P5.1.1.c_Y3_TG+EnnB1_ANSES “TG+ enniatin B1” will start. Details per project: - Project P5.1.1.a_Y1_Toxins_BfR_UNIVIE: The enniatins A, A1, B and B1 as well as Beauvericin have testing priority. Alternariol, Alternariol monomethylether, Altertoxin I, Altenuene, Tentoxin and Tenuazonic acid are among the prioritized compounds for the Alternaria study program. The in vitro studies agreed upon natural toxins (enniatins and Alternaria toxins) to close data gaps will include genotoxic, endocrine and immunotoxic effects, as well as other potential endpoints/target organs. Overall, the studies will provide needed in vitro data and identify critical toxicological effects of enniatins and Alternaria toxins. Experimental work will start for some test substances in late Y2, and for some substances in early Y3 due to the sourcing process including DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 52 the procurement process that was very time consuming. Due to the delays in obtaining the test substances a 1-year extension of the project length has been required in Y2, therefore, the planned ending date for this project is now M48. We are in contact with the scientific officer from the feed and contaminants unit from EFSA regarding the availability of data on enniatins and beauvericin program since EFSA is searching for new data to possibly update its current opinion. We are in contact with the OECD AOP project to exchange information. [Participants: BfR, UNIVIE, NIB, SCIENSANO, INSA, UNAV, ISS, BPI, INRS, NVI, STAMI, NIPH, IMR, ANSES, WU-TOX, Fraunhofer-IBMT, TUB] - P5.1.1.b_Y1_BPA_HumTox_BfR: The test substances for the set of in vitro studies are: BPZ, BPE, BPP, BPAP, BPPH, and BPS-MAE. The WP5 experts also agreed on using BPA as a reference substance and for metabolism halogenated analogues as TBBPA and Pergafast 201). We have a delay, due to the time taken in hiring the personnel and acquiring the BPA alternatives in a centralized manner and are currently requesting an extension of 18 months for this project. Results will be shared with Physiologically Based Pharmacokinetic (PBPK) modelers in 5.3. We are in contact with both ECHA, RIVM and Health Canada/Ontario University to avoid duplication of efforts. Contact has been made with the EURION cluster regarding endocrine disruption studies. Y3 experimental work for each of the five endpoints: 1. Endocrine effects: In vitro Human H295R Steroidogenesis Assay (OECD TG 456) (ISS), effect of BPA and alternatives in thyroid hormone synthesis key events using in vitro test (under consideration by EURL ECVAM (ISCIII), and analysis of the data by assay (i.e., calculation EC50 and benchmark dose (BMD) values, fold changes) (ISS, INRAE, ISCIII). 2. Developmental Neurotoxicity: In vitro screening of cellular effects of BPA and BPA alternatives (CNRS, INRAE), molecular analyses for the identification of relevant biomarkers (CNRS, INRAE, LIH), epigenetic analyses for the identification of relevant biomarkers (LIH), and data analyses, identification of biomarkers, proposition of new AOPs / implementing existing AOPs (CNRS, INRAE, LIH). 3. Immunotoxicity: Identification of immune cell targets and effects of bisphenols on immune functions (UMIL), investigation of the relationship between bisphenols immunotoxicity and their effect on the inflammation-induced tryptophan breakdown and related immunobiochemical pathways (MUI), to investigate the relationship between bisphenols immunotoxicity and their effect on the glucocorticoid system (ULFFA), and to provide new mechanistic data for AOP development, by evaluating the effects of BPA analogues on the intracellular calcium homeostasis of both resting and stimulated immune cells (ISS). 4. Carcinogenicity: In vitro test as foreseen in the battery of genotoxicity testing (INSA, ISS), in vitro genotoxicity of BPA and BPA alternatives and relevant metabolites will be assessed on hepatic 2D and/or 3D (spheroids) cell models developed from HepG2 using micronucleus, comet and transcriptomic assays (collaboration with T5.2a) (INSA, IBMT, NILU), non-genotoxic carcinogenicity of BPA and BPA alternatives will be assessed by Bhas 42 cell transformation DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 53 assay (following OECD guidance document) (INRS, INSA, ISCIII, TTL, NILU). 5. Metabolism bioactivation routes and kinetics: In vitro study of the metabolic fate and bioactivation pathways of key BPA alternatives (INRAE) and absorption studies with intestinal models as input of PBK modelling (ISS). [Participants: ISS, UMIL, INRAE, TTL, ULFFA, MUI, ISCIII, INRS, Fraunhofer-IBMT, CNRS, LIH, SDU, NILU, INSA] For both projects 5.1.1a and 5.1.1.b, we are in close contact with partners within PARC, especially 5.2, 5.3 and WP6 to exchange data. - P5.1.1.c_Y3_TG+ EnnB1_ANSES: The purpose of this project will be to fill an in vivo data gap on Enniatin B1 identified by EFSA by conducting a TG408 study. The tissues originating from this study will also be used for further analyses. In parallel, the work on Enniatin performed on NAMs will increase regulatory confidence in the corresponding approach. A 5-d study may also be conducted using enniatin B1, as proof of concept of using transcriptomic data to estimate health-based guidance values. [Participants: ANSES, BfR, NIPH, INSA, INSERM, TUB, UNAV] A5.1.2 Toxicity assessment addressing data gaps of concern (Environment) Details per project: - P5.1.2.a_Y1_NaturalToxinsAqua_Ugent: Mixtures of natural toxins, including both cyanotoxins and mycotoxins, will be tested during Y3. Selection of mixtures will be based on results of the toxicity testing with single compounds carried out in Y1 and Y2. Specifically, the following OECD tests will be carried out with mixtures of natural toxins: (1) OECD 243: Lymnaea stagnalis Reproduction Test (SLU) (2) OECD 211: Daphnia magna reproduction test (UGent) (3) In close collaboration with (2), acute exposure experiment on the same mixtures with Daphnia will be conducted to assess behaviour and transcriptomics. (UoB) (4) OECD 201: Freshwater Alga and Cyanobacteria, Growth Inhibition Test (Chlorella vulgaris) (UAVR) (5) OECD: harpacticoid copepod development and reproduction test with Nitocra Spinipes (UGent). Exposure scenarios for invertebrates will be conducted through water exposures to pure toxins or dietary exposure of mixture of toxin-producing strains ordered from certified culture collections (e.g., same strains as used for individual testing). [Participants: SLU, UGent, UAVR, UOB] - P5.1.2.b_Y1_BPAalternatives_BPI_MU: Toxicity testing of bisphenol alternatives selected during Y1 on certain organisms has been started and will continue during Y3. It is noted that the experimental work started with a delay mainly due to time-consuming procedures followed for chemicals order (centralized order for all PARC partners) and difficulties faced by several partners in hiring personnel. Therefore 6 more months of the project's duration is requested. A DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 54 list of 26 assays (OECD TG, ASTM and ISO) will be conducted by the involved partners covering a wide range of organisms (e.g., fish, aquatic invertebrates, alga, marine bacteria, earthworms, soil microorganisms, xenopus, C. elegans) and effects (e.g., acute effects, effects on reproduction and on endocrine system). In Y3 we will mainly focus on experiments with mixtures. The mixtures to be tested will be selected based on the results of tests with individual substances (carried out during Y1 & Y2). In addition, the mixtures will be selected considering also the occurrence of bisphenols in different environmental compartments (i.e., surface water, soil, sediment) as revealed by reviewing the available literature data (review article will be published in Y2) and the results from monitoring activities that will be carried out in the frame of PARC WP4. [Participants: BPI, SLU, IISPV. SDU, INERIS, NIB, IEP-NRI, UU, UG-PL, UAVR, EAWAG, NIVA, UFZ, SU, Cefas-Defra] Task 5.2: Innovative methods and tools for toxicity testing and modelling Co-leaders A5.2.1: DTU (DK), VUB (BE), Co-leader A5.2.2: MU (CZ) Participants: Activity 5.2.1: AIT (AT), ANSES (FR), BfR (DE), DTU (DK), IfADo (DE), INRAE (FR), INSA (PT), INSERM (FR), IRFM (IT), ISCIII (ES), IUF (DE), LIH (LU), LIST (LU), MU (CZ), MUI (AT), NIB (SI), NILU (NO), NIPH (NO), NMBU (NO), NCPHP (HU), RIVM (NL), SDU (DK), TiHo (DE), UAntwerpen (BE), UFZ (DE), UG-PL (PL), UIBK (AT), RPTU (DE), UKON (DE), UL-LACDR (NL), ULFFA (SI), UNAV (ES), UOB (UK), UU (SE), UU-IRAS (NL), VUA (NL), VUB (BE), WR (NL) Activity 5.2.2: BfG (DE), BPI (EL), EAWAG (CH), IISPV (ES), INERIS (FR), MU (CZ), MUI (AT), NIB (SI), NIC (SI), NIVA (NO), SDU (DK), SLU (SE), UAntwerpen (BE), UFZ (DE), UG-PL (PL), UPO (ES), CSIC (ES), INRAE (FR) A5.2.1 Innovative methods and tools for toxicity testing and modelling In the preceding year, after having installed the project and recruited skilled personnel, emphasis was primarily on chemical selection and initiating lab work. Looking forward to the upcoming year, priorities will pivot towards the substantive development of wet lab operations and the associated generation and dissemination of results. Details per project: - P5.2.1.a_Y1_NGTXCs_INRAE: The development of tests that can identify tissue and substance specific effects related to distinct aspects of non-genotoxic carcinogenesis will be continued in Y3. In general, given the distinct throughput possibilities of the various test systems, at least two and up to 10 substances will be tested for the 5 different MoA selected (proliferation, cytotoxicity inducing regenerative proliferation, nuclear receptor activation, inflammation and changes in cellular morphology indicative for cell migration). The data will be compiled and analysed to identify specific Mode of toxic Action (MoA) than can be detected by different assays, including a comparison of the minimal concentration needed to detect a significant effect. The DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 55 compilation and analysis of the data will reveal the need for optimization of assays and facilitate the development of an efficient testing battery. The set-up of novel NAMs for identified gaps in the assessment of non-genotoxic carcinogens (NGTXC) will be initiated. [Participants: INRAE, BfR, ANSES, INSERM, NIB, UL-LACDR, UNAV, IRFM, RIVM, RPTU, NILU, MU] - P5.2.1.b_Y1_MD-EDC_BfR: An extended spectrum of substances from the priority families has been assessed in Y2 and will continue in Y3, including major metabolites and breakdown molecules, allowing further MoA exploration, as well as AOP and read-across development synergies. Exploration of nuclear receptor (NR)-driven effects will continue focusing on the characterization of prioritized BPA alternatives (BPZ, BPE, BPP, BPAP, BPPH, and BPS-MAE. The WP5 experts also agreed on using BPA as a reference substance and for metabolism halogenated analogues as TBBPA and Pergafast interaction with the nuclear receptors PPARy, PXR, CAR, and RXRα using stable reporter cell lines and biophysical approaches (crystallization, 3D structure determination). Similar to Y2, in Y3 several articles characterizing the interaction of bisphenols and their halogenated analogues with different nuclear receptors will be written. Developments in the human mesenchymal stem cells models (2D/3D), as well as with BPA alternatives effects on adipocyte (human, murine) and in zebrafish models will continue in Y3. The effects of selected substances on triglyceride accumulation in liver cells will be analysed and work on an in vitro phospholipidosis assay using human liver cells will be continued. Moreover, involvement of mTOR signaling in metabolic disruption will be further explored, as well as the potential of mTOR-related assays to detect MDC. Due to some delays in the overall project progress in the initial phase of the project as e.g. resulting from difficulties in recruiting personnel, a 1-year extension of the project is necessary to complete the envisaged tasks. Actions /Experiments: 1. Structural and functional study - Extended assessment of Nuclear Receptor (NR) activities testing (PPARy, PXR, CAR and RXRα) using transfected cell lines, and application of this testing strategy to major BPA alternatives, metabolites and other compounds (INSERM). 2. In vitro assays for screening MBD using different cell types established and tools for MTOR signaling characterisation (BfR, UIBK, UU-IRAS, UFZ, UU, IfaDo). 3. Whole organism - Development of early life stage zebrafish metabolic disruption test (UAntwerpen). [Participants: INRAE, BfR, INSERM, IfaDo, UU-IRAS, UAntwerpen, UU, UIBK, UFZ] - P5.2.1.c_Y1_EDThDisruption_DTU: Characterization of the molecular mechanisms and assays that can be exploited for NAM -Thyroid Hormone System Disruptors (THSD)- testing will be continued in Y3. Already initiated in vitro and in silico assay developments will continue. An OATP3A1 overexpressing cell line will be tested for its capacity to assess compounds interfering with TH transport across the blood-cerebrospinal fluid barrier (BCSFB). In addition, the currently established in vitro choroid plexus organoid model will be further characterized and used to test suspect EDCs for their capacity to interfere with TH transport across the BCSFB. Quantitative DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 56 Structure Activity Relationship (QSAR) development of the models for inhibition of MCT8, DEHAL1, TTR and TRHR will be finalized and applied to screen a large inventory of chemical substances, including 13,406 REACH-registered substances. Data analysis of data from the in vivo multi-organ transcriptomics will be performed. A toxicogenomic comparison between in vivo effects in the developing rat liver and in the human stem cell-based hepatocyte in vitro assay will be performed to assess cross-species and assay translatability. The evolutionary conservation of the Thyroid Hormone System (THS) axis will be further characterized to make better use of non-human NAMs to inform on human health risks. The literature review to extrapolate THSD from fish/amphibians to mammals/humans is ongoing. The feasibility and appropriateness for developing a bisphenols case study will be assessed based on literature data availability. [Participants: DTU, VUB, BfR, SDU, UAntwerpen, VUA, ISCIII, INSERM] - P5.2.1.d_Y1_Immunotox_Inserm: In year 3, based on the first results from the set-up of in vitro systems and the in vivo experiments, work on developing specific NAMs will continue. In Y3, work will focus on pre-selected most relevant methods, compared to Y2 where the pre-screening was performed. In the different in vitro systems relevant for respiratory immunotoxicity, NAM concept will be finalized and characterized for their usefulness and limitations to come to a testing strategy (MUI, NCPHP, RIVM, LIST). To determine common markers of immunosuppression and response to vaccination, studies in human, animal and in different primary cells and cell lines will be further combined to identify the most relevant in vitro or ex vivo system for human health (INSERM, NIPH, INSA, LIH). Studies on NAMs and assays for immunotoxic events by (mixtures of) model or priority compounds including mycotoxins and bisphenols (table below) will be continued to support the build-up of AOPs and IATAs (UL-FFA, UFZ, WR). Biocides chloramine-T, piperazine BPA alternatives BPA, BPS-MAE, BPZ, BPB, TCBPA, BPAP, Bis-Z, BPPH, BPG, BPS-MPE, PF201, BTUM, BPE, BPP Mycotoxins Deoxynivalenol, fumonisin B1, aflatoxin B1, enniatin A, A1, B, B1, ochratoxin A, zearalenone, alternariol, tenuazonic acid, tentoxin Therapeutic substances dexamethasone, chloroquine, sirulimus (rapamycin), cyclosporine A, tacrolimus (FK506), doramapimod, Hydrocortisone, dapsone Perfluorinated substances PFAS, PFOA, PFOS Other BP3, MIKB, B[a]P The report released by ECHA (Key areas of Regulatory Challenge) in June 2023 mentions DIT (Developmental Immunotoxicity) as a priority for the development of related NAM to assess the potential hazard of substances. Some discussions have been engaged (intra and inter projects through PARC) and will continue to include DIT in the frame of this project. A meeting is planned in spring 2024 with interested partners as well as ECHA and CAAT. This project will be delayed by 12 months due to recruitment difficulties. The new end date of this project is M48. DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 63 UAntwerpen (BE), UGent (BE), UG-PL (PL), UKHSA (UK), UKCEH (UK), VUB (BE), WR (NL), WU-TOX (NL) A6.1.1: Development of IATAs for regulatory purposes In Y3, we will continue the development of IATAs for the ‘low-hanging fruit' endpoints, i.e. genotoxicity, endocrine disruption (with a focus on (1) thyroid hormone system disruption and (2) antiandrogen activity) and liver toxicity (with a focus on liver fibrosis) for selected regulatory framework(s) and specific population groups. Based on the outcome of the mapping exercise on the availability and maturity (i.e. the level of completeness) of existing AOPs and existing NAMs, and the extent to which these NAMs have already been mapped to AOPs for these endpoints, AOP networks (AON) have been created; these will be refined in Y3. Where sufficient information is available, AON are being (partially) quantitated; this work is also continued in Y3. The IATAs will be based on human relevant AOPs/AONs. Additionally, the work on a workflow for human relevance assessment will be continued in Y3. Both the work on this workflow and the IATA development for genotoxicity, endocrine disruption and liver toxicity will be an iterative process consisting of various cycles of optimization, thereby taking into account the feedback from different stakeholders (A6.1.3). For the IATAs, the progress made, issues encountered and the draft IATAs will be reported in AD6.9 (UL-LACDR, M30). This additional deliverable is delayed from M24 to M30, to allow for inclusion of the draft IATAs. Details per project: - P6.1.1.a_Y1_HumanRelevance_RIVM: This project is focused on a pragmatic workflow for the assessment of human relevance of AOPs and the relevance of NAMs related to the key events (KEs) or key event relationships (KERs) of the pathway under study. In Y3, the project will continue the work on the case studies initiated in Y2 to further improve the workflow. The case studies initiated comprise AOP#54 (Inhibition of NIS leading to learning and memory impairment) and AOP #162 (Enhanced hepatic clearance of thyroid hormones leading to thyroid tumors). Improvements will be achieved by making use of relevant existing approaches for weight of evidence assessment and uncertainty analysis. This will be done in close collaboration with WP7. The improved version of the workflow and the case studies performed will be described in a scientific manuscript. Additional case studies related to the IATAs for endocrine disruption will be performed, to provide insights on the human relevance and to identify possible aspects that need further improvement. To allow for dedicated discussions on the workflow and the case studies performed a face-to-face stakeholder workshop will be organized in Autumn 2024 (see A6.1.3). [Partners: AUTH (EL); RIVM (NL); ENSP (PT); BPI (EL); WU-TOX (NL); NIPH (NO); STAMI (NO); IRSN (FR); ISS (IT); IISPV (ES); LIST (LU)] - P6.1.1.b_Y1_IATA-ED_UAntwerpen: IATA development for endocrine disruption. In Y3, this project will continue to integrate information on readiness of methods from external activities such as OECD TDM EG and perform additional readiness assessments if required. An inventory of AOP networks for thyroid (THSD) and anti-androgenicity (AA) has been completed. Based on these networks we are refining the draft IATAs for THSD and AA. A workshop will be held in early Summer 2024, in collaboration with the regulatory stakeholders (primarily ECHA and EFSA), to discuss the available options including individual test method decision criteria for developing DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 64 Defined Approaches, based on current regulatory priorities and future needs. The development of quantitative KERs, if required, will be focused on critical linkages in the AOP networks / conceptual IATA models. Finally, case studies to evaluate the draft IATAs and to initiate discussion around development of Defined Approaches will be designed and initiated in Y3. [Partners: UAntwerpen (BE); UKHSA (UK); MU (CZ); AUTH (EL); UGent (BE); INSERM (FR); UL-LACDR (NL); RIVM (NL); ISS (IT); DTU (DK); SDU (DK); LIST (LU); BPI (EL); UG-PL (PL); IISPV (ES); STAMI (NO); KI (SE); IRFM (IT); ENSP (PT); Sciensano (BE); CEFAS-DEFRA (UK)] - P6.1.1.c_Y1_IATA_GENTOX_Sciensano: IATA development for genotoxicity. In Y3, this project will continue to characterize KERs within the AOP network for genotoxicity based on evidence collected via systematic reviews. We will develop, to the extent possible, a qAOP for DNA alkylation leading to increases in mutations and structural and numerical chromosome aberrations and characterize the uncertainties related to genotoxicity methods. Also, we will identify the main drivers of variability. Based on all these activities, the project will design an IATA for genotoxicity. This project will also design and execute an initial case study for genotoxicity, including existing as well as newly generated data. [Partners: Sciensano (BE), INRAE (FR), VUB (BE), UL-LACDR (NL), WU-TOX (NL), ISS (IT), IBMT (DE), UG-PL (PL), STAMI (NO), LIST (LU), BPI (EL), IRSN (FR), RIVM (NL), KWR (NL), NILU (NO), IRFM (IT), NIPH (NO), WR (NL), MUI (AT)]. - P6.1.1.d_Y1_IATA_STOT_UL-LACDR: IATA development for liver toxicity. In Y3, building on the inventory of existing (draft) AOPs and AOP networks and associated NAMs relevant for liver fibrosis, this project will design a draft IATA for liver fibrosis. In order to evaluate the draft IATA, dedicated case studies for liver fibrosis will be designed and initiated. These case studies include collection of existing data as well as generation of new data using relevant NAMs. This will be done in close collaboration with WP5 and related research initiatives. For the draft IATA and initial case studies, we will benefit from the initial quantification of AOPs related to fibrosis. In collaboration with RISK-HUNT3R, qAOP development for liver fibrosis on the basis of existing in vivo data will be finalized in Y3, while quantification of AOPs related to fibrosis based on data generated in the project initial case study and literature data will be continued in Y3. [Partners: UL-LACDR (NL), WU-TOX (L), INSERM (FR), Ugent (BE), AUTH (EL), MU (CZ), IISPV (ES), STAMI (NO), ISS (IT), IRFM (IT), WR (NL)] A6.1.2: Evaluation of IATAs through case studies The draft versions of the IATAs for genotoxicity, endocrine disruption and liver toxicity as well as the draft workflow for human relevance assessment developed in A6.1.1 will be evaluated through (additional) case studies. Under the coordination of the case study leaders, case study teams will investigate the case study regulatory hypotheses that were defined in Y1 and Y2 with the selected relevant case study compounds. Regarding uncertainty analysis and weight of evidence assessment, we will closely collaborate with WP7. This will be achieved through joint case studies/use cases, where both WPs bring in their own expertise. First candidates have been identified in the project on human relevance (P6.1.1.a_Y1_HumanRelevance_RIVM). For ultimate integration of the data into QIVIVE, we will further strengthen the link with the experts DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 65 and tools established in T5.3. For the latter, dedicated discussions in Spring/Summer 2024 will be organized between T6.1 and T5.3, with the aim to determine how to best organize this collaboration. Reports on the case study modeling and experimental activities will be submitted for review via the project management system under T2.1 (M36). In the IATA case studies, the lessons learned by different stakeholders from previous case studies mapped in T6.3 will also be implemented as soon as this information becomes available. [Partners: AUTH (EL), BPI (EL), CEFAS-DEFRA (UK), DTU (DK), ENSP (PT), Fraunhofer (DE), IISPV (ES), INRAE (FR), ISS (IT), KI (SE), KWR (NL), MU (CZ), MUI (AT), RIVM (NL), SCIENSANO (BE), SDU (DK), UAntwerpen (BE), UG-PL, UKHSA (UK), UL-LACDR (NL), VUB (BE), WR (NL), WU-TOX (NL)] A6.1.3: Stakeholder engagement For each of the health effects addressed we will continue the interactions with relevant related (research) initiatives, such as EURION, EU-ToxRISK, RISK-HUNT3R, ONTOX, PrecisionTOX and HESI GTTC, established in Y1 and Y2. For a wider stakeholder involvement, the progress made on AOP/AON and IATA development for genotoxicity, endocrine disruption and liver toxicity as well as on the workflow for human relevance will be discussed with a diverse group of stakeholders in the annual two-day WP6 workshop. For the design of the case studies related to the IATAs as well as the workflow for human relevance, we will again actively seek input from ECHA, EFSA, JRC and OECD, to maximize regulatory impact. This will be achieved through online meetings. Additionally, ECHA, EFSA, JRC and OECD will be consulted regarding the additional IATAs for complex endpoints (described in AD6.1 (M24)), in terms of considerations to be taken into account when designing projects for Y4 and beyond. Additionally, we will organize a physical meeting with regulatory stakeholders in Autumn 2024, with the aim to explicitly collect their feedback on the work done, issues encountered and possible next steps. [Partners: RIVM (NL), Sciensano (BE), UL-LACDR (NL), STAMI (NO), ISS (IT), UG-PL (PL), BPI (EL)] Task 6.2: Integrative exposure and risk assessment Co-Leaders: ANSES (FR), VITO (BE) Partners: AU (DK), ARSO (SI), AUTH (EL), BPI (EL), CSTB (FR), DTU (DK), EFSA (IT), EHESP (FR), ENSP (PT), FINBA (ES), TTL (FI), FMUL (PT), FOPH (CH), Fraunhofer (DE), GEoSZ (SI), ICPS (IT), CSIC (ES), IISPV (ES), KI (SE), INERIS (FR), INRAE (FR), INRS (FR), INSA (PT), IRFM (IT), ISCIII (ES), ISSeP (BE), IUSS (IT), IVL (SE), KWR (NL), LNS (LU), MOH-CY/SGL (CY), MU (CZ), NIJZ (SI), NIOM (PL), NIPH (NO), NLZOH (SI), OI (SI), ONIRIS (FR), OVAM (BE), RIVM (NL), SRU (NL), SCIENSANO (BE), SECO (CH), SLU (SE), STAMI (NO), TNO (NL), UAVR (PT), UBA (DE), UGR (ES), UG-PL (PL), UNIPD (IT), UNISANTE (CH), USI (CH), UoB (UK), UU-IRAS (NL), WR (NL) Synergies between T6.2 projects case studies (PFAS, pyrethroids and metals) will be deployed during year 3 to propose an integrative and dynamical way to model mixture exposure and perform health impact assessment. For example, developments and implementation in Parc ToolBox of PBPK models from P6.2.2.a_Y1_PBPK_INERIS will serve into P6.2.1.a_Y1_SourcetoDose_VITO, P6.2.3.a_Y1_RealLifeMixtures_RIVM and P6.2.1.b_Y1_Aggregate_ANSES to convert doses and enable model verification. Also, DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 66 aggregate exposures from P6.2.1.b_Y1_Aggregate_ANSES will be used to identify the main sources that contribute to the risk related to mixtures in P6.2.3.a_Y1_RealLifeMixtures_RIVM. In addition, during year 3, the project leaders and the case study leaders will start discussing the impact of the case studieswith regulators from DG SANTE, DG ENVI, DG EMPL. The case study results should not might be sensitive for regulators and may raise concern in society. Regulators may then timely provide answers on possible risk mitigation measures. Furthermore, regulators should be informed timely and before publications are out in the public. Task 6.2 leaders will discuss synergies with EFSA’s Chief Scientific Officers and leader and experts of EFSA knowledge and innovation communities (KIC). The expected synergies are related to risk interpretation of mixture risk assessment using HBM data and aggregated exposure. EFSA is working on the ExpoAdvance strategic roadmap. Depending on the outcome of this Roadmap report, task 6.2 leaders will discuss potential work for EFSA and for PARC related to aggregated exposure and sources of exposure. Four deliverables will be delivered by month 36.  D6.1 Report on aggregate exposure for general population and workers, and source to dose models applied to case studies (P6.2.1)  D6.2 Report on innovative methods based on PBK models (P6.2.2)  D6.3 Report on innovative approaches for real-life mixture RA (P6.2.3)  D6.4 Report on health impact indicators and their policy implications (P6.2.4) A6.2.1 Aggregated exposure assessment from multiple sources and routes for general population and workers Details per project: - P6.2.1.a_Y1_SourcetoDose_VITO: from the inventory of source-to-dose models for the general population, the existing model parameters and the gap analysis (models and data for model parameters), the development of realistic models (for identified gaps) will continue. This involves the translation of the mechanistic understanding of source-to-dose exposure into conceptual models, for two aspects (i) exposure to chemicals released from consumer products and materials to the indoor environment (general population), and (ii) direct and indirect exposure via release and transfer from the outdoor environment. Case studies have been started in Y2. In Y3, we will continue elaboration of the case studies. The case studies are organized by chemicals and by type of environment (indoor and outdoor). Case studies for the outdoor environment (PFAS and metals) involve 1) case studies in hotspots in participating countries (hotspots, being complementary to general population background exposure for metals and PFAS covered in P6.2.1.b_Y1_Aggregate_ANSES), and 2) transfer-specific aspects for general population exposure (e.g. transfer from soil to crops and subsequent dietary exposure). Case studies for the indoor environment focus on model parameterization and validation for phthalates and other plasticizers. Other possible case studies will be presented and selected in Y3 (in view of gaps, PARC chemical priorities and policy needs). Case studies include several aspects: set up of scenarios, model parameterization, model runs and interpretations, verification of model outcomes, and policy implications (e.g. innovative methods for setting health-based soil standards built on epidemiological data). Deliverable D6.1 (developed together with 6.2.1b) is foreseen for M36, and scientific publications on case studies will be written in Y3. [Lead: VITO DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 67 (BE); LNS (LU); Contributors: RIVM (NL); ANSES (FR); IVV (DE); CSTB (FR); KWR (NL); IVL (SW); NIJZ (SI); FOPH (CH); GeoZS (SI); FMUL (PT), IISPV (ES), OVAM (BE); ISSeP (BE), ARSO (SI)]. - P6.2.1.b_Y1_Aggregate_ANSES: the strategy to assess aggregate exposure through different sources from general and occupational environments and different routes of entry (inhalation, dermal, ingestion) will continue to be developed and implemented in case studies (All partners). In collaboration with T8.3, selected exposure models from the scoring process that has followed the inventory of the associated models and tools will be connected in the ParcToolBox. This is the part of the ParToolBox on integrative models such as MCRA and kinetic models for reverse dosimetry to link HBM data (internal exposure) to external exposure).A training on aggregated exposure will be organized by WR-BIOM with the help of at least ANSES, UNISANTE, RIVM, FOPH, TNO, TTL. The development of case studies will continue with the analysis of the data collected, and the combination of the heterogenous datasets to sustain aggregated cases studies for the two selected metals (Cd and CrVI), selected pesticides (e.g. the pyrethroids), the PFAS and the phthalates. Aggregate exposures and associated risk will be produced for several European populations. The innovative approach developed to aggregate exposures and its application to several case studies will be part of a second deliverable at the end of year 3 and several scientific publications will start. Several meetings by project subworking groups (method/functional design/model inventory/different case studies) are planned at least every two months and at least one preferably physical meeting for the whole project. [Lead: ANSES (FR) Unisanté (CH). Case study/method lead : ANSES (FR), UNISANTE (CH), WUR-BIOM (NL), TNO (NL), TTL (FI), IVL (SE), ISCIII (ES), FOPH(CH) Contributors: CSTB (FR), INRS (FR), CSIC (ES), IISPV (ES), INSA (PT), ENSP-UNL (PT), FMUL (PT), VITO (BE), ISSeP (BE), OVAM (BE), LNS (LU), SRU (NL), WR-BIOM (NL), KWR (NL), IVV (DE), MU/RECETOX (CZ), NIOM (PL), NIJZ (SI), GeoZS (SI), ARSO (SI), BPI (EL), AUTH (EL), UOB (UK), NIPH (NO), STAMI (NO), AU (DK), EFSA (EU), UoB (UK)]. A6.2.2 Modelling exposure through life Details per project: - P6.2.2.a_Y1_PBPK_INERIS: In the first two years, an inventory of PBPK models and their gaps, as well as refinement in PBPK models to account for lifetime exposure in terms of physiology and exposure routes were made for pesticides (pyrethroids and organophosphates), metals (Cd, As, Pb, Hg), bisphenols and PFAS. In year 3, the aim is to extend the parameterisation of PBPK models for these compounds to address identified gaps and needs for human lifetime exposure, including sensitive populations: (i) description of in utero exposure and the placental transfer process based on the physicochemical properties of the different compounds (INERIS, AUTH, IISPV, ANSES, RIVM, SLU), (ii) description of physiological changes at different stages of development and pregnancy (INERIS, AUTH, IISPV, ANSES, RIVM, SLU, TNO), (iii) including maturity of detoxification or transport processes (INERIS, AUTH, IISPV, ANSES, RIVM, SLU, TNO), (iv) integration of gender-specific differences for both physiological and Absorption, Distribution, Metabolism and Excretion (ADME) processes (INERIS, AUTH, IISPV, ANSES, RIVM, SLU), (v) transfer across the blood-brain barrier (AUTH, IISPV, ANSES, RIVM, SLU), (vi) inclusion of new compartments in PBPK models to account for new biomarkers predicting specific DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 68 exposure, such as the concentration of chemicals in hair (e.g., MeHg) (AUTH, IISPV, ANSES, RIVM, SLU, INERIS) and (vii) implementation of models in the integrative ParcToolBox (MCRA/Integra) in collaboration with T8.3 (WR-BIOM). Extensive parameterisation of newly generated data in PARC (e.g., in WP5) will continue. To facilitate the use of PBPK models in other T6.2 projects, training sessions will be organised in year 3. One whole meeting is expected to be organised every 3 months, and one meeting per thematic working group every 2 months.[Lead: INERIS (FR), AUTH (EL); working group lead: IISPV (ES), ANSES (FR), ONIRIS (FR), TNO (NL). PFAS case study: IISPV (ES), WR (NL), SLU (SE), NIPH (NO), INERIS (FR), VITO (BE), RIVM (NL), TNO (NL). Metals case study: ANSES (FR), AUTH (EL), ONIRIS (FR). Bisphenols case study: AUTH (EL). Parameterisation working group: ANSES (FR), ONIRIS (FR), AUTH (EL), SLU (SE), INERIS (FR), IISPV (ES), IRFM (IT), RIVM (NL). Exposure routes working group: TNO (NL), IISPV (ES), VITO (BE), INERIS (FR), SLU (SE), RIVM (NL). Implementation of models: WR-BIOM (NL), ANSES (FR), ONIRIS (FR), RIVM (NL). Other contributors: IVL (SE)] A6.2.3 Mixture exposure and risk assessment Details per project: - P6.2.3.a_Y1_RealLifeMixtures_RIVM: the year 3 will be consecrated to the application of the developed strategy in each case study (e.g., pesticides and neurotoxic effects, PFAS and immune effect, metals and kidney effects, metals and developmental effects) to perform mixture risk assessment (MRA) using several HBM dataset from different European general and occupational populations. The case studies will be extended to cover mixtures of substances from different chemical families regarding real-life exposure and common health effects. For that, a set of real-life of mixtures crossing regulatory silos will be produced from combined exposures by applying statistical methods on selected HBM studies. Additional hazard and kinetic data will be collected to group the new selected chemicals in assessment groups. The started work on comparing statistical methods to study the link between mixtures biomarkers of exposure and health effects will continue. The integration in the PARCToolBox (MCRA) of the input data (HBM, hazard, kinetic parameters), the statistical and kinetic models as well as the updated risk metrics needed for each case studied will be improved and tested during the application phase. The MCRA Integrated Risk Assessment Dashboard as part of the PARC Toolbox will be extended with occupational data and risk interpretation. Partners with HBM data will be trained to be able to perform MRA on their own dataset. Training will be also given to stakeholders and synergy will be discussed in particular with EFSA and ECHA. The proposed strategy to perform MRA and its application to case studies will be part of a second deliverable at the end of year 3 and several associated publications will start during year 3. The project will offer tools, concepts and realistic examples/case studies on how the risk assessment can be innovated. Case studies will show impact for selected regulatory silos (prioritized chemical families). In year 4 this might be extended with chemicals overarching regulatory silos. Work will be performed in close cooperation with WP7 (linked to the project and via data champions), T4.1 for data generation and analysis, WP5 for newly hazard data and T8.3 for the development of the model network. Case study leaders will contribute to PARCopedia. Three project meeting comprising physical meeting are planned and one meeting for each case study will be yield every 6 weeks. Regular meetings between case studies leaders will be also conducted. [Lead: ANSES (FR), RIVM (NL). Case study and method WG lead: ANSES (FR), RIVM (NL), BPI (GR), UGR (ES), VITO (BE) Contributors: AU (DK), AUTH (EL), CSIC (ES), IISPV (ES), DTU DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 69 (DK), EASP (ES), EFSA (EU), EHESP (FR), FINBA (ES), ICPS (IT), JSI (SI), INERIS (FR), INSERM (FR), ISCIII (ES), IVL (SE), LNS (LU), MOHCY/SGL (CY), MU (CZ), NIJZ (SI), NIPH (NO), SRU (NL), SLU (SE), STAMI (NO), TTL (FI), UBA (DE), UG-PL (PL), UNIPD (IT), UU-IRAS (NL), VITO (BE), WR (NL), INRAE (FR), KWR (NL), FMUL (PT), GeoZS (SI), UNIVIE (AT), IRFM (IT) INRAE (FR), Oniris/INRAE (FR)]. A6.2.4 Human health impact assessment and risk indicators In this task on environmental burden of disease (EBD) and health impact assessment (HIA) the project on case studies (P6.2.4.c_Y1_HIACaseStudies_ UU-IRAS) functions currently as a central hub to which other projects (P6.2.4.a_Y1_HIADataAvailability_VITO; P6.2.4.b_Y1_HIAMethod_UU-IRAS; P6.2.4.d_Y1_HIAIndicators_VITO) are linked. Starting from the case studies, data are gathered to perform environmental burden of disease (EBD) calculations, hurdles in the methodology are described and indicators are developed when finalizing the case studies. Deliverable D6.4 is foreseen for M36, consisting of all performed work regarding methodological improvements, data availability, case studies, and indicators on health impact assessment and burden of disease. Overarching project meetings will be organized with all partners every 2 months, and each case study will have roughly meeting every 4/6 weeks. Details per project: - P6.2.4.a_Y1_HIADataAvailability_VITO: in Y3, the project will continue the exploration of possibilities to gather data and fill data gaps for data-poor chemicals identified and prioritized in year 1. In Y3, focus will be on exposure data (external & internal), health data, exposure-response data and data on socio-economic status. The availability of data will be linked to the case studies where starting from the individual case studies, data and data gaps will be identified. A quick scan of newly available health impact assessments and environmental burden of disease calculations, exposure data, and exposure-effect functions necessary for the case studies will be performed in Y3. Additional data gaps to be addressed in the course of PARC will be identified and prioritized. [Project lead: VITO (BE) UU-IRAS (NL). Contributors: ANSES (FR), AUTH (EL), DTU (DK), ENSP (PT) , FMUL (PT), IISPV (ES), INSA (PT), ISSeP (BE), IVL (SE), KI (SE), MU (CZ), NIJZ (SI), NIPH (NO), NLZOH (SI), OI (SI), SRU (NL), Sciensano (BE), STAMI (NO), USI (CH)] - P6.2.4.b_Y1_HIAMethod_UU-IRAS: the project will continue the activities related to exposureeffect relationships initiated and elaborated in year 1 and 2 : inventory of existing exposurebiomarker of effect-health outcome relationships, analyse possibilities for incorporation of effect biomarker measurements as surrogate markers for toxicity associated with chemical exposure which would allow health impact assessment for (pre)clinical outcomes, development of an integrative approach to take different lines of evidence (in vitro, in vivo, and human data, mode of action, biomarkers of effect) into account to establish human relevant exposure-effect relationships, addressing all associated uncertainties, and development of a Weight-of-evidence (WoE) approach for selection of exposure-effect functions including information from epidemiological, toxicological and mechanistic studies. A manuscript on the methodological challenges for calculating the EBD related to chemical exposure has been initiated in Y2 and will be finalized in Y3. Case studies in Y2 focusing on the burden of disease will be analysed for hurdles towards methodological aspects. In Y3, extension of the case studies towards calculations of costs for society will be included, depending on the specific case studies. Oher methodological improvements identified and prioritized in year 1 and 2 may be initiated as well DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 70 in Y3; feasibility of addressing those during the course of PARC will be assessed and activities will be planned accordingly. [Project lead: UU-IRAS/UBA Contributors: ANSES (FR), AUTH (EL), DTU (DK), ENSP (PT), FMUL (PT), IISPV (ES), INSA (PT), IVL (SE), KI (SE), MU (CZ), NIPH (NO), OI (SI), RIVM (NL), Sciensano (BE), UBA (DE), USI (CH), UU-IRAS (NL), VITO (BE), WR- (NL)]. - P6.2.4.c_Y1_HIACaseStudies_ UU-IRAS: the first case studies to calculate health impact, burden of disease, risk/benefit and/or cost/benefit focusing on chemicals, exposure-(biomarker of) effect relationships, exposure scenarios, and methodological improvements and innovations prioritized in year 1, were running during year 2 and most will be finalized during year 3. Case studies already running in year 2 are:  Pyrethroid exposure and association with ADHD (leading partner VITO)  Environmental burden of a mixture of heavy metals on cancer and cardiovascular related mortality in adults living close to waste incinerators (leading partner FMUL)  EBD of arsenic exposure and cancers (lung, bladder & skin) (leading partner Sciensano)  HIA of lead exposure and cardiovascular diseases and chronic kidney disease (leading partner DTU)  Influence of waste co-incineration in a cement plant on cancer burden (leading partner OI)  Lead (Pb) and methylmercury (meHg) and IQ loss in Children in Europe for single substance and for mixtures (Leading partner ANSES) Case studies already discussed in Y2 and starting in Y3 are exposure to PFAS and related immune effects (leading partner VITO), cadmium and chronic kidney disease (leading partner Sciensano, RIVM) and possibly exposure to dioxins and reduced fertility (leading partner DTU). Other possible case studies starting in Y3 will be presented and selected through a multi-criteria decisions analysis tool developed during Y1. [Project lead: ANSES (FR), VITO (BE) Contributors: AUTH (EL), BPI (EL), DTU (DK), ENSP (PT), FMUL (PT), IISPV (ES), INSA (PT), KI (SE), NIPH (NO), OI (SI), SRU (NL), Sciensano (BE), SPF (FR), STAMI (NO), UU-IRAS (NL)]. - P6.2.4.d_Y1_HIAIndicators_VITO: in year 3, the project will focus on the development and implementation of indicators (proposed in year 1 and 2) to assess the human health risk and/or impact of selected exposure scenarios to inform policy makers. In Y2, input was given to EEA for the development of risk indicators for BPA and for pesticides, In Y3, we will continue developing indicators (for other substances, cfr. case studies), which will aid the translation of science to policy and answer policy-related questions (e.g.; in collaboration with EEA). Main focus will be on indicators coming from the case studies. [Project lead: VITO (BE) UU-IRAS (NL) Contributors: ANSES (FR), FMUL (PT), Sciensano (BE), DTU (DK), OI (SI), VITO (BE) Contributors: , AUTH (EL), ENSP (PT), INSA (PT), IVL (SE), MU (CZ), NIJZ (SI), , UU-IRAS (NL), WR (NL)]. DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 71 Task 6.3: Review of risk assessment methodology Co-Leaders: SU (SE), BPI (EL) Partners: UCL (UK), INSA (PT), EAA (AT), EAWAG (CH), TTL (FI), FOEN (CH), INERIS (FR), INSERM (FR), INRAE (FR), IRFM (IT), ISS (IT), ISSeP (BE), JSI (SI), KI (SE), LSMU (LT), DTU (DK), REGIONH (DK), UCPH (DK), RSU (LV), SCIENSANO (BE), STAMI (NO), NILU (NO), SYKE (FI), UBA (DE), ULUND (SE), VUB (BE), UNIBAS (CH), KEMI (SE), SU (SE), BPI (EL), UMIL (IT), UNIPD (IT), EFSA (EU), UT (EE) The initiated projects will continue during M25-M36, with further refinement of reviews and analysis through case studies as well as further exploration of stakeholder interactions. The interactions with ECHA, EFSA, SCCS, JRC and OECD on their involvement in the task, either to follow or actively take part in specific case studies, will continue, focusing both on input to ongoing and planned work as well as to disseminate results and increase regulatory uptake. Possibilities to disseminate results to national authorities will be explored. The need to describe regulatory relevance of the projects and case studies will continuously be highlighted. Case studies will be ongoing for two to five years. Due to delays related to e.g., recruiting PhD students, obtaining data, and handling overwhelming amounts of literature data, three case studies (CS2, CS13, and CS19) planned to end in M24 will continue also in Y3 and three case studies (CS12, CS17, and CS18) planned to end M36 will continue in Y4. One additional case study (CS20) will be initiated M25. One to two project meetings to present and discuss the progress of the case studies will be organized during Y3 [Partners involved: SU (SE), BPI (EL), KEMI (SE), All partners]. Case study-specific meetings for planning and progress updates will be organized by the case study leaders as needed. A6.3.1 Substance and effect specific reviews - P6.3.1.a_Y1_SubstanceRA_SU; Case studies reviewing substance-specific RA depending on intended use. The reviews of substance-specific assessments depending on intended use will continue through two case studies. The case studies are described below and will evaluate differences and similarities, and subsequent implications, across legislations. The outcomes of this project may serve as a ground for adjustments of the relevant regulations. The identification of dissimilarities in testing requirements and hazard assessments of substances depending on specific uses will offer valuable information for the implementation and potential impacts of the “One Substance One Assessment” approach on regulations targeting specific uses of chemicals. Further, the potential barriers and opportunities, and available methods, for harmonisation in a systematic way will be presented. [Partners involved: SU (SE), UCL (UK), SCIENSANO (BE), IRFM (IT), KI (SE)].  CS12_MethodOSOA_SU: In this case study, we will perform an analysis of risk assessment processes, including significant differences between processes, strengths of the current system(s), and potential gaps, overlaps, or inefficiencies. We have performed a mapping of substances regulated in more than one regulation and we will from that select a number of substances to investigate further how lack of harmonization across DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 72 regulations impact the risk assessment and subsequent risk management. (SU (SE), KI (SE))  CS13_PlasticizersRA_UCL: During Y3, we will assess the implications of similarities and differences in approaches to hazard, exposure, and risk assessments in 37 pieces of legislation listing at least one of 417 plastic additives (according to EUCLEF). Justifications for differences in overall approach (not in assessments of individual substances), e.g., in relation the balance of risks and benefits for a specific intended use and/or availability of alternatives, will be reviewed, as will potential and available solutions for harmonization. This aims to highlight barriers and opportunities for the implementation of the OSOA ambition of the CSS, using plastic additives as a case for which there will be a multiplicity of intended uses and correspondingly relevant chemical regulations. Due to a delay in obtaining data the end date has been extended from M24 to M36. (UCL (UK), SCIENSANO (BE), IRFM (IT)).  CS14_BiocidesRA_SU: M1-M24 (finalised). (SU (SE), KI (SE)). - P6.3.1.b_Y1_EffectRA_BPI; Case studies reviewing effect-specific RA: The reviews of effectspecific assessments will continue through six case studies. The case studies are described below and will include aspects such as sensitization and developmental neurotoxicity as well as use of non-animal methods for identification of endocrine disruption, genotoxicity, and carcinogenicity. The project will evaluate and suggest opportunities for improving and harmonising aspects of risk assessment methodology, including in vitro short-term tests and structure-activity based methodologies. The project will analyse and discuss relevant gaps and research needs and, when relevant, propose improvements and harmonization of the testing requirements, criteria, recommendations, and best practices across EU regulations. The results will be made available to and discussed with regulatory agencies. These case studies reviewing risk assessment methodology concerning specific priority endpoints will contribute to conclusions on the need for innovation in regulatory risk assessment to rapidly and effectively identify chemicals with hazardous properties for human health and the environment through a more effective, accurate and harmonised across silos OSOA approach. [Partners involved: REGIONH (DK), STAMI (NO), SU (SE), IRFM (IT), UNIBAS (CH), VUB (BE), ISS (IT), NILU (NO), INSA (PT), BPI (EL), KI (SE), INSERM (FR), INERIS (FR), EAA (AT), UBA (DE), INRAE (FR), UT (EE)].  CS9_SKINSENSIRISK_REGIONH: Year 3 will be devoted to finalising the systematic review of components in risk assessment methods, including the IATAs described by OECD (Guideline 497) and QRA2 adopted by Scientific Committee on Consumer Safety (SCCS), mixtures and gaps of knowledge. Further the specific case study on successes and failures in risk assessment of skin sensitizers will be initiated. Results will be used for suggesting improvements in regulatory practices across areas and highlight gaps of knowledge. (REGIONH (DK), STAMI (NO), SU (SE), IRFM (IT), UNIBAS (CH)).  CS10_ED-cosmetics_VUB: The critical analysis of risk assessments will continue during the third year using (a) selected candidate(s) of the SCCS priority endrocine disruports list (ED) list. The results obtained in this case study will be discussed with the SCCS and a reporting of the safety evaluation modus operandi of the selected substances will be done. During a final meeting with the relevant stakeholders, recommendations and best practices will be formulated with respect to the inclusion of NAMs and new technology to cover the biological complexity and as such enable the prediction of human health effects for substances with potential ED activity (VUB (BE), INRAE (FR)).  CS11_GenotoxCarc_ISS: Year 3 will be devoted to finalizing the revision and comparison DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 79 prioritization of case studies. (Lead partner: UT. Participants: INERIS, IRFM, ISS, NIPH, NIVA, UG-PL, UKCEH, UNIBAS, EA, KEMI). Project action 1, Y3 short description: Research priorities and requirements will be finalized and the survey is in progress (the round of responses ended by the start of Y3) and results are under analysis; one to two publications is foreseen. (partners involved: UT, UG-PL, IRFM, UNIBAS, NIPH, ISS, INERIS, KEMI) Project action 2, Y3 short description: A more in-depth analysis of the existing knowledge of datadriven ML or AI QSARs is conducted, and corresponding publications are in the writing phase, two publications are in preparation. (partners involved: UT, UG-PL, IRFM, ISS, INERIS, KEMI). Project action 3, Y3 short description: As part of previous activity description of a framework for more transparent reporting of predictions obtained using ML & AI models for regulatory purposes will continue in Y3. (partners involved: UT. UG-PL, IRFM, UNIBAS, NIPH, ISS, INERIS, UKCEH, NIVA, EA, KEMI) Project action 4, Y3 short description: Work for the selection of case studies will start in Y3 (partners involved: UT, INERIS, IRFM, ISS, NIPH (VKM), NIVA, UG-PL, UKCEH, UNIBAS, EA, KEMI). A6.4.3. Developing information transfer structures and enforcement methodology for chemicals in articles to support the transition to a circular economy Biweekly meetings with all partners will be held to monitor and discuss the progress of individual actions steering towards the overarching aim of A6.4.3. Focused working meetings will be held in between the biweekly meetings when needed. A connection with ECHA forum for enforcement has been established to continuously receive feed-back on the methods being developed under 6.4.3b and dissemination of the results. Dissemination will also occur via the agencies directly involved in the project (KEMI and TUKES). Details per project: - P6.4.3.a_Y1_SuProM_MU will be continued, with the completion of two ADs and one report outlining the current screening and enforcement structures for chemicals in articles and how chemical hazards are incorporated in LCA (AD6.14: Report on current screening and enforcement structures – Leader: TUKES (M28); AD6.15: Report on existing database structures with recommended structures (M36) Report on LCA incorporation of chemical hazards - Leader: MU (M36). A prolongation has been agreed with the CT for the report and AD originally planned for M24. Results from mapping activities regarding existing data structures relevant to substances in products and materials will be synthesized and summarized in a research article. Case studies testing the information structures for retrieving information for enforcement and supporting chemical hazard assessment in LCA models will be completed. (Lead partner: MU: Participants: KEMI, Rise, TUKES, VUA, VITO, TNO). Planned year 3 of PARC: Short description of next planned key project action 1: Synthesizing and summarizing results from the evaluation of data sources for enforcement and testing methods. Results from surveys and interviews performed during Y2 will be interpreted and gaps and needs related to analysis of chemicals in product and overall enforcement structures will be identified. Recommendations DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 80 for optimized structure of enforcement activities and project ideas will be summarized in a report AD6.14. Partners involved: MU, RISE, KEMI, TUKES, VUA. Short description of next planned key project action 2: Testing the existing information structures and tracking how data produced in response to regulatory structures and enforcement is stored in the systems. Based on the review of databases performed during Y2 the ability to generate comprehensive occurence data will be tested for 1) chemical class and (2) product class. The results will be summarized together with the review in AD6:15 (M36). Partners involved: MU, RISE, KEMI. Short description of next planned key project action 3: Case study on how current information structures on chemicals in materials and articles can be used as input to Life cycle assessment (LCA) models for evaluation of chemical hazards. Information on chemicals in Life cycle inventories will be reviewed to assess the completness of existing databases compared to other sources reviewed in Y2. The impact of data quality on LCA toxicity assessment will be evaluated and areas for improvement will be identified. The results on LCA assessment of chemical footprints and data needs will be summarized in a report (M36); Partners involved: MU, RISE, KEMI. - P6.4.3.b_Y3_ENFORCE_KEMI will be initiated during Y3. The project will evaluate the applicability of methods of chemical identification for use in the enforcement of chemical safety legislation, to fulfil crucial needs raised in project 6.4.3a. For effective enforcement rapid screening methods that cover a wide range of restricted/SVHC substances that can be applied to a variety of sample matrices are typically needed. In evaluating methods, this project will further test to what extent databases reviewed in P6.4.3a capture the chemical composition of articles. By developing and applying rapid analytical techniques for screening and validation the project will provide a proof-of-concept methodology that could be used in enforcement of chemicals legislation The project will have a specific focus on additives in high volume plastics and perand polyfluoroalkyl substances in articles identified as major use categories. Lead partner: KEMI, Participants include MU KemI, RISE, TUKES, VUA, New partners in A6.4.3 SU and ORU Planned Y3 of PARC. Short description of next planned key project action 1. Testing of recently developed methods and interlaboratory comparison of selected products for PFAS analysis will be conducted for different product matrices. Product categories to be tested for PFAS will be selected based on their relative importance for environmental emissions and near-field exposure for consumers. Analysis will be performed by using available in-house methods for the same samples to evaluate the agreement of PFAS measurements between laboratories. Lead partner KEMI, Participants include MU, RISE, TUKES, VUA, SU and ORU Short description of next planned key project action 2. Analytical methods for rapid screening of plastics will be developed based on the needs identified under P6.4.3a. Plastic product categories to be tested will be selected based on annual production numbers and quality of databases describing presence of chemical additives (e.g., construction plastics or vehicle plastics). A methodology based on data base searches by product category and polymer type DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 81 together with suspect screening using mass-spectrometry will be developed and tested. Lead partner MU, Participants include RISE, TUKES, VUA, ORU A6.4.4. Risk assessment to support and promote efficient overall protection of biodiversity Details per project: - P6.4.4.a_Y3_CRNCS1_KEMI : Science-policy scoping workshops with stakeholders will be used to continue to develop the Technical report outlining the regulatory needs for ERA development areas (Report title: Clarifying regulatory needs for advancing the environmental risk assessment of pesticides). Activity 6.4.4 follows an iterative, collaborative knowledge-building process coordinated through the CRN project. Stakeholder views will be gathered through online surveys and workshops at European, national, and regional levels. This feedback will be used to update the first existing report by refining the problem formulation, assess the current ERA framework for pesticides, and shape the continued research in PARC 6.4.4 projects. Coordination and alignment with regulatory needs will continue to be strengthened with WP 2, in particular Task 2.2 projects PARCopedia and NGRAroute, and with WP3 on communication and dissemination to stakeholders, inlcuding EU and national authorities. In this context, also the mapping of projects of relevance within PARC and external projects will thus be pursued during year 3 in order to establish new and deepen existing collaborations. Currently a survey is being conducted to capture views on the current ERA framework among regulatory environmental risk assessors working with plant protections products under Regulation (EC) No 1107/2009. The survey is sent to more than 300 recipients in national authorities and EFSA. The survey results will be presented and discussed in follow-up workshops with regulatory risk assessors in September 2024. A key WS objective is to engage regulatory risk assessors in the collaborative knowledge-building process and ensure regulatory relevance of the research in PARC 6.4.4. The ongoing survey is conducted in collaboration with Horizon Europe projects Syberac and PollinERA, with the aim to synergize stakeholder engagement strategies as well as concrete activities. The project will also continue to coordinate the four other projects in PARC A6.4.4 with regular coordination meetings with project leaders, Forum for Exchange meetings and an Activity 6.4.4 Workshop. AD6.7: Technical report outlining the regulatory needs for ERA development areas. (M36 delay from originally planned M24. The rationale for the proposed delay is that project P6.4.4.a made agreement with EFSA to align and coordinate stakeholder commitment and input (survey and workshops). This to avoid duplication of work from both PARC, EFSA and stakeholders to be invited. To align with EFSAs timeplan the first workshop needs to be delayed till after month 24.) (Lead partner: KEMI Participants: UBA, FOEN, EFSA, ANSES, UOS, ULUND, NIVA) - P6.4.4.b_Y3_PPPEXPCS2_UFZ Extension of existing project from M24 to M36. Findings reported in the technical reports produced during year 2 will be used to identify the most relevant factors for predicting PPP concentrations in surface waters within agricultural catchments as well as potential impact on predictive power of regional differences in key environmental properties. During year 3 we will close remaining knowledge gaps and ensure regulatory feasibility. We will include additional data from supporting databases in the data analysis (e.g. geo-referenced soil properties), further improve the curation of exposure monitoring data sets to eliminate DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 82 confounding factors and study artefacts and the inclusion of additional substances covering a wider range of physico-chemical properties. In the beginning of year 3 feedback from regulatory experts will also be gathered (in collaboration with project 6.4.4.a) on opportunities for improved reality-benchmarking and potential to reduced complexity in regulatory surface water exposure models. The feedback from regulators will be included in the further scoping of research questions to be explored during year 3. Moreover, the Exposure project will strengthen a cross disciplinary link between exposure modelling and effects monitoring by performing a dedicated study on benchmarking predictions based on Toxicokinetic-toxicodynamic (TKTD)-modelling and alternative approaches to aquatic effects monitoring with the SPEAR-index. This study will provide further information on an appropriate level of detail in predictive modelling for aquatic exposure. The technical reports from year 2 will during year 3 be developed into Additional deliverable AD6.20 (Technical report on factors and processes needed to be included in robust aquatic exposure predictions for regulatory use, including an assessment of geographic representativeness), based on the above mentioned results and with expert feedback from stakeholder workshops. Lead partner: UFZ (DE) Participants: SLU (SE), Fraunhofer IME (DE), UOS (DE), EAWAG (CH), NIVA (NO), ULUND (SE), IEP-NRI (PL), UoB (UK). Regulatory core group: KEMI (SE), UBA (DE), FOEN (CH), ANSES (FR), EFSA (EU).) - P6.4.4.c_Y3_PPPEFFCS3_UFZ will continue to expand the meta-database with information and data that are species related (e.g. ecological, traits), site related and methods related (e.g. omics data, Pict and Spear concepts) from national and EU-level sources. Network within PARC WPs and externally through partners will continue to be used to identify monitoring and active substance effects data sources. Using this data the project will inform on factors and processes needed to be included in the ERA to obtain an improved balance between reduced complexity and increased ecological realism. Moreover, the project will continue to test exposure models against monitoring data to support the interpretation of effects assessments in the field. In the beginning of year 3 feedback from regulatory experts will be gathered on implications of possibilities and solutions for improved reality-benchmarking and potential reduced complexity of exposure models This will be done in workshops coordinated with P6.4.4.a. The feedback from regulators will be used to define new research questions to close knowledge gaps and ensure regulatory feasibility. The project will be reported in AD 6.8 Report informing on factors and processes needed to be included in the ERA to obtain an improved balance between reduced complexity and increased ecological realism. (Lead partner: UFZ Participants: UC (PT), EAWAG (CH), SLU (SE); UKOLD (DE); ULUND (SE), NIVA (NO), UCLM (ES), UOS (DE), ISCIII (ES), Regulatory core team: KEMI (SE), UBA (DE), FOEN (CH), EFSA (EU), ANSES (FR), UKCEH (UK)). - P6.4.4.d_Y3_PPPBENCHCS4_ RPTU will continue to build a database for comparable risk quotients of authorised and non-authorised PPPs. Collected substance toxicity and physicochemical data from the current ERA regulatory process have been compiled, and use data for exposure calculations have been retrieved from national pesticide registries in different member states. Based on these data alternative ways to conduct comparable ERAs will be tested and benchmarked to monitoring and field data in collaboration with project 6.4.4.c and 6.4.4.e. Prototype comparative databases will be used as templates for further development. (Lead partner: RPTU Participants: UFZ, ISCIII, NIVA, EAWAG and ULUND). Regulatory core team: KEMI (SE), UBA (DE), FOEN (CH), ANSES (FR), EFSA (EU)) DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 83 - P6.4.4.e_Y3_PPPOSCS5_ISCIII Case studies in ES, FR, PL, and NO reflecting different agricultural landscape conditions and climates will be conducted during year 3. The case studies will generate field-based data designed to test a generic conceptual model for landscape environmental risk assessment for pesticides and other stressors. Alongside with this generic model other prospective ERA methods and models, such as exposure and effect predictor models will be tested in the case studies. (Lead partner: ISCIII Participants: UFZ (DE), RPTU (DE), NIVA (NO), IEP-NRI (PL), OFB (FR), UCLM (ES), ULUND (SE), Uni Osnabrück UOS (DE), UOB (UK), UKCEH (UK), EA (UK), UAVR (PT), SYKE (FI), INERIS (FR), UC (PT), EAWAG (CH), Regulatory core team: KEMI (SE), UBA (DE), FOEN (CH), ANSES (FR), EFSA (EU)) Deliverables: D6.1 1st Report on aggregate exposure for general population and workers, and source to dose models applied to case studies (P6.2.1.a_Y1_SourcetoDose_VITO, M36 and P6.2.1.b_Y1_Aggregate_Anses, M48) – Leader: ANSES (M36) D6.2 1st Report on innovative methods based on PBK models (P6.2.2.a_Y1_PBPK_INERIS_AUTH, M48) – Leader: AUTh (M36) D6.3 1st Report on innovative approaches for real-life mixture RA (P6.2.3.a_Y1_RealLifeMixtures_RIVM, M48) – Leader: RIVM (M36) D6.4 1st Report on health impact indicators and their policy implications (P6.2.4.a_Y1_HIADataAvailability_VITO, M66; P6.2.4.b_Y1_HIAMethod_UU-IRAS, M66; P6.2.4.c_Y1_HIACaseStudies_UU-IRAS, M42; P6.2.4.d_Y1_HIAIndicators_VITO, M42) – Leader: VITO (M36) Additional Deliverables3 AD6.7 Technical report outlining the regulatory needs for ERA development areas (P6.4.4.a_Y1_CRNCS1_KEMI, M42) – Leader: KEMI (New delivery date M36) AD6.9: Report on draft IATAs and associated case studies (P6.1.1.a_Y1_HumanRelevance_RIVM, M36; P6.1.1.b_Y1_IATA_ED_UAntwerpen, M36; P6.1.1.c_Y1_IATA_GENTOX_Sciensano, M36; P6.1.1.d_Y1_IATA_STOT_UL-LACDR, M36) – Leader: UL-LACDR (New delivery date M30) AD6.14: Report on current screening and enforcement structures (P6.4.3.a_Y1_SuProM_MU, M36) –Leader: TUKES (New delivery date M28) AD6.15: Report on existing database structures with recommended structures (P6.4.3.a_Y1_SuProM_MU, M36) - Leader: MU (M36) AD6.16: Status of integration and use of NAMs in the EU chemical regulatory risk assessment landscape – a mapping exercise and gaps & needs analysis (P6.4.2.a_Y1_LandscapingSurv_UNIBA, M36; P6.4.2.b_Y1_NGRApractice_VKM_NIPH, M36; P6.4.2.c_Y1_NAMAM_UT, M36) - Leader: UNIBAs (New delivery date M36) 3 AD6.17 (Optimizing regulatory risk assessment and management of chemical mixtures in Europe) and AD6.18 (Dealing with mixtures in regulatory risk assessment through the use of monitoring data and NAMs) will be postponed from M36 to M40 due to the delay of the projects P6.4.1.a_Y1_OPREMIXCS1_BRUNEL_UGot and P6.4.1.b_Y1_MONAMMIXCS2_UFZ, delayed from M36 to M40. DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 84 AD6.19 Technical report informing on factors and processes needed to be included in the ERA to obtain an improved balance between reduced complexity and increased ecological realism. (P6.4.4.c_Y1_ PPPEFF CS3_UFZ, M36) – Leader: UFZ (M36) AD6.20 Technical report on factors and processes needed to be included in robust aquatic exposure predictions for regulatory use, including an assessment of geographic representativeness. (P6.4.4.b_Y3_PPPEXPCS2_UFZ, M36) – Leader: UFZ (M36) WP N° WP7 Lead Beneficiary VITO/UOB WP title FAIR Data Partn er N° 1 1.1 1.6 1.10 4 6.1 8 9 15 15.2 20 24.3 25.1 25.2 25.4 25.7 26 26.4 27.2 31 32 34.5 35.2 35.12 36 49 59 Partn er short name ANSES INSERM INRS BRGM VITO IMROH MU UZIS UBA UFZ ISS UniLU KWR TNO UL-LACDR WR NIPH NIVA UG-PL JSI NIJZ IISPV KI UU AUTH EFSA UOB PM/ partne r 24.7 3.1 1.5 7.5 32 2 80 0.6 5.5 5 4 8 1.1 4.1 2.4 1.3 2 4 4.1 29.7 6 30 0.50 5 7 2 5 Start M25 End M36 Objectives The main goal of WP7 is to support innovation and transparency in chemical Risk Assessment (RA) through improved exchange and re-use of data between different RA actors and disciplines, and through innovative data analytical approaches. The specific objectives of WP7 for year 3 are: - Task 7.1: o Updating the DMP with clusters of project-level DMPs, using the online DMP tool; o Finalisation of a scientific paper on the PARC Fair Data Policy (PFDP) o Finalisation of white paper on PARC FAIR ambitions and implementation roadmap; o Continuous “training through doing” for Data Champions, Liaisons and FAIR Implementation Taskgroup (FIT) on use of online DMP tooling to ensure proper collection of project specific DMPs, to build the PARC domain-specific and cross-domain tools to enable FAIR metadata and data - Task 7.2: o Consolidation of the FAIR PARC data hub and expanding it with new functionalities; o Implementation of identified data management use cases and ongoing identification of new use cases o Enrichment of the set of controlled vocabularies at PARC level, as well as domain-specific standards o First steps towards implementation of cross-domain interoperability framework for CRA o Consolidation and reporting on the approaches, tools and instruments developed in the first three years - Task 7.3: DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 85 o Selection and initial implementation of identified uncertainty and data analysis use cases and ongoing identification of new use cases. o Development of user guidelines for different statistical analytical (meta-, pooled etc.) techniques and demonstration of the utility and feasibility of different approaches via the selected use cases. o Gap analysis of uncertainty assessment methodologies and demonstration of the process with domain specific uses cases. o Development of a harmonised FAIR evidence representation framework for computed entity associations o Building a consistent data exchange schema according to the FAIR principles to integrate and assemble information from wider sources. o Harmonising use of existing and new ontologies in text mining for AOP development. Scoping, gap analysis and initial benchmarking of data / knowledge mining and AI/ML tools. o Enriching existing background knowledge resources for chemical risk assessment through multi-modal data analysis. Description of Programmed Activities Task 7.1: FAIR Data policy and implementation Co-leaders: TNO (NL), UOB (UK) Partners: ANSES (FR), BRGM (FR), VITO (BE), MU(CZ), UZIS (CZ), UBA (DE), ISS (IT), KWR (NL), UL-LACDR (NL), NIVA (N), UG-PL (PL), JSI (SI), KI (SE), AUTH (EL), ISSEP (BE) Sub-contractors: GFF (BE) No project submitted for this task A7.1.1 PARC Data Policy and Data Management Plan The first version of the PARC FAIR data policy was finalized (M18), although some key issues need further elaboration, including the detailed analysis of the European Open Science Cloud (EOSC) FAIR data levels, and how achievable these are for the different sub-domains of PARC, which will be addressed in Y3. The initial PFDP will be reformatted into a scientific paper. For this, the content will be augmented with [1] possible unidentified additional topics (using an AI model on internet resources) and [2] a semi-quantitative analysis of the relevance of different PFDP topics for different stakeholders, using text mining approaches. [Partners involved: KI, UBA, KWR, UoB, VITO, TNO, JSI, ISS and EFSA; support of GFF]. In collaboration with WP2 (PARCopedia) the PARC WP7 Glossary of key terms will be maintained and continuously updated as the various WP7 use cases produce formalised vocabularies This, to ensure that the various A-Zs presented in PARCopedia are fully consistent and aligned with these community developed standards that are agreed with the domain experts from across PARC WPs 4-8 and formalised via the controlled vocabularies. [Partners involved: UoB, KWR, MU]. An ongoing activity throughout Y3 will be implementation of the project-level DMPs. The initial data management sections of the PARC project proposals and implementation plans (developed DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 86 in Y2) will be further elaborated, documented via the selected online DMP tool (Data Stewardship Wizard), into the final project DMPs, summarising how data have been managed, stored, archived and made FAIR. The WP7 data liaisons (see also T7.2) will support the responsible partners in the projects from the R&I WPs (e.g., represented by the Data Champion) to fill in the project specific DMPs (after training) [Partners involved: VITO, UOB, MU, UG-PL, UL-LACDR, IISPV, AUTH, TNO, ISSEP, UFZ, KI, UBA, JSI]. This work will directly feed into starting with updating and reviewing the overarching DMP (1st review of the Data Management Plan, due M42) [Partners involved: TNO, ANSES, VITO, UBA, UL-LACDR, MU, ISS]. The process for monitoring of the KPI on the number of datasets FAIRifed will be extended as outlined in D1.3. A7.1.2 Communication and Training: organisation and delivery across PARC4 The dedicated training programme has been completed in Y2, led by Go Fair Foundation (GFF), resulting in a set of Data Liaisons and FAIR implementation Task group will be delivered, leading to sets of facilitators and trainers able to deliver additional training in FAIR Implementation Profiles (FIP), and Metadata 4 Machines (M4M). As part of this training, the participants will develop the domain-specific FIPs for PARC, as well as develop tools and solutions to support the implementation of FAIR in PARC. [Partners involved: ISSeP, UL-LACDR, MU]. Ongoing communication and dissemination (including hands-on training) of WP7 activities – at WP, Task and Project levels, and support of data management across-WPs is needed on a continuous basis. Building on the extensive feedback during Y2, we have undergone a reorganisation of the approaches to engaging and communicating with WPs and project clusters. The training approach will be less theoretical and more hands-on and focussed on the specific datasets and experimental approaches utilised by the various projects and their partners in Y3. [Partners involved: ISS, UL-LACDR]. The FAIR Implementation Team (see also T7.2) has implemented a process for finalising documentation and deployment (roll-out) of the tools and approaches to increase data management efficiency and facilitate data use and re-use within PARC and beyond. As tools / approaches are finalised and documented, including with WP-specific training materials, these will be rolled out to WPs / project clusters via hands-on training sessions tailored to the needs of the individual WPs / project clusters, on a rolling basis. Deployed and documented tools will also be discussed with WP2 for integration into PARCopedia, with WP8 for integration into the SSbD Toolbox, with WP9 for integration into the PARC-wide training activities and inventories, and WP3 for communication and dissemination beyond PARC. [Partners involved, PL-UG, ISS, MU]. A7.1.3 FAIR Data Use Case Coordination For increased consistency and follow up this activity has been integrated into activity 7.2.3. Task 7.2: Data libraries 4 The name of the activity was modified compared to AWPY2. The previous name in AWPY2 was: Training and organisation DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 87 Co-Leaders: MU (CZ), VITO (BE) Partners: ANSES (FR), AUTH (EL), BRGM (FR), EFSA (EU), EV-ILVO (BE), IISPV (ES), ISS (IT), ISSeP (BE), JSI (SI), KI (SE), MU (CZ), NIVA (NO), UFZ (DE), UG-PL (PL), UBA (DE), ULLACDR (NL), UNILU (LU), UOB (UK), UU (SE), UZIS (CZ), KWR (NL), WR (NL) Sub-contractors: GFF (NL) For Task 7.2 two projects were submitted in Y1. These projects encompass a broad and integrated approach towards two specific a prirori identified domains and cut across the different activities defined under 7.2. Additional to these projects, use cases, where possible clustered for specific domains, are identified through the established horizontal links between WP7 and R&I WPs and projects, and are added on a rolling basis. Therefore, no additional projects have been defined. Actions related to these additional use cases and clusters identified in Y2 are added under the respective activities A7.2.1 to A7.2.4 as transversal activities. - P7.2.2.a_Y1_chemicals-in-environment_MU_VITO [Participants: MU, VITO, UFZ, BRGM, UniLU, ISSEP, JSI, ANSES, NIVA, UBA, KWR, AUTH]. The project is linked to activities under 4.2 (multiple exposure monitoring, PFAS baseline use case and ECDs) and specific activities under 6.4 such as the collection of existing exposure monitoring data on pesticides and chemicals in the articles and to some extent with A7.2.1 (the environmental component of the CRA landscaping). Within the project, existing synergies between major data platforms/networks will be further supported (IPCHEM, NORMAN, GENASIS). The collaboration with NORMAN established in Y2, and will continue in Y3, as NORMAN has been identified as one of priority platforms for environmental data reuse and storage. New synergies will be established and supported to harmonize the (meta)data exchange templates, workflows, metadata standards, vocabularies, with the aim to increase the community data FAIRness. Pipelines will be set up to share datasets generated or compiled in PARC with IPCHEM. The (meta)data structure analysis will also feed the PARC FAIR Data Hub environmental component. Further on, broadening the landscaping to other matrices/other priority chemicals will take place once the whole process is completed for the first set of priority substances (PFAS, EDs, pesticides)/matrices (e.g., water) and it will allow the WP7 team to test the approach, further improve the landscaping exercise and assess the expected efforts needed when broadening to other matrices and substances and consequently also improve the design of future use cases. A communication with other WPs will continue to identify potential use cases. The use cases will further be analyzed by the use case management group, prioritized, and implemented according to their priority. In Y3, the project will also focus on linking the environmental data with the HBM data in close collaboration with the 7.2.2.b project, and on building and promoting FAIR enabling and FAIR supporting resources for environmental data. The as-is FAIR Implementation Profiles (FIPs) will be consecutively assessed for major resources according to their priority, and they will serve as a basis to build a community reference FIP. DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 88 - P7.2.2.b_Y1_HBMdatasets_VITO [Participants: VITO, MU, UU, UBA, ISSeP, JSI, WR]. The WP7 HBM data project will build on the Y1 and Y2 selection of relevant HBM datasets and linked communities, and the roadmap for FAIRification that has been developed (see table 1.4). Projects that will use these datasets include different 4.1.1 activities (HBM survey, monitoring and occupational hazards), Activity 4.1.3 (Guidance Values) and Activity 4.1.4 (HBM Data Analysis) in WP4, several WP6 projects (A6.2.3 -real life mixturesand A6.4.1 -regulatory risk assessment- ) and the T8.2 (Early Warning Systems) and T8.3 (risk modelling network) Tasks in WP8. Table 1.4: Planned actions for P7.7.2.b in Y3 As mentioned, domain-specific clusters have been identified in Y2, among which data management activities on toxicology data. Activities on toxicology data will be coordinated by Parts (Schedule) Actions Participant Institution(s) (Country) 1. Transfer HBM4EU to PARC (M1 to M36) Operation of PEH platform VITO 2. Use case management (M1 to M42) Use case working group VITO, MU, UBA, ISSEP, JSI, WR Collaboration/exchange with IPCHEM VITO Collaboration with other related data initiatives VITO, MU 5. Implementation and testing (M18 to M42) Implement use of data model, metadata schema and ontology Set up HBM data platform and services, integrating tools and pipelines for harmonization, processing and quality control of existing and newly generated datasets; integration with models (WP8); pipeline for sharing of data with IPCHEM (and, in future, the EEA); connection to geospatial data; connection to environmental data; HBM dashboard Depending on the outcome of the “Assessment of federated systems for privacy-preserving analysis” set up a pilot case with HBM data VITO, MU, ISSEP, JSI, WR, UU DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 95 2. Dataset from EFSA using human Peripheral blood mononuclear cells (PBMCs) from healthy volunteers exposed to reference compounds inducing specific stress responses. The effects will be captured using transcriptomics, dynamic imaging and FACS analysis. 3. Dataset from Exposome-Scan NL using the HepG2 test system exposed to a library of oxidative stress inducers. Imaging, metabolomics and transcriptomics data will be collected. Concentration-response effects of high throughput transcriptomics, metabolomics and functional imaging (using fluorescent reporter cells) will be assessed at different time points. 4. Data set from PARC WP5/task 5.2 using engineered hiPSC cells expressing fluorescent cell proliferation markers differentiated into mammary glands and exposed to a series of non-genotoxic carcinogens. Phenotypic image-based approaches will be complemented by high throughput targeted mRNA sequencing using ©TempO-Seq. - While much effort will be made in standardizing and harmonizing the data production and collection workflow, the integration tools mentioned in the scoping review will be used for these heterogeneous datasets. Use case 4 (Lead: NIVA, Partners involved: IISPV): Case study to integrate heterogenous environmental exposure and effects data into a (cumulative) risk assessment workflow by 1) Standardise and harmonize reporting of environmental exposure and ecotoxicological bioassay data into controlled vocabularies and ontologies (T7.2.2a), 2) Develop GUI based import formats and data repositories to FAIRify data for consistent reporting, mapping, transfer and linkage between data sources (T7.2.2a), 3) Develop data and metanalysis pipelines to integrate (A7.3.1), analyse and visualize heterogeneous data sets representative of Aggregated Exposure Pathways (AEPs) and Adverse Outcome Pathways (AOPs) (A7.3.2, A7.3.3, A7.3.4) and 4) identify and parametrize selected Source to Outcome Pathways (STOPs) for environmentallyand regulatoryrelevant exposure scenarios. The proposed work is anticipated to involve different environmetnal exposure scenarios, be organized as a multi-year iniative that aligns with activities in tasks 7.3.17.3.4 and in extension supports developing the PARCopedia model environment (WP8.3 and P8.3.2.a) Use case 5 (Lead: UOB, Partners involved: IISPV) Enriching existing background knowledge resources for chemical risk assessment through multi-modal data analysis. This use case will develop a methodology and workflow that is bottom-up and can be applied across WPs / projects easily. It is a multi-year use-case that spans across Tasks 7.3.1-7.3.4 but is presented here as its overarching goal is development of enhanced methodologies for data FAIRification for risk assessment. Key steps will include: 5a. Development of an approach to enable generation of “provenance networks” for scientific datasets and facts through post hoc analysis, which can be considered as a means of 'retrospectively FAIRifying science' by establishing the provenance of data/facts/etc. Given that many of the PARC projects are using literature curated datasets / grey literature, this sub-task will also explore opportunities for tracking the spread of false information (e.g., down-playing toxicity of specific chemicals or sensationalisation of results, or identification of subsets of data that contribute to overfitting for example). DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 96 5b. Based on the landscape mapping performed in T7.2.1, prioritised pubmed / biomedical / toxicological databases will be parsed for relevant toxicological entities (based on the community agreed ontology / structured vocabulary developed in Task 7.2.2); Following this, UoB will use our novel methods for identifying significant associations between pairs or groups of terms, such as sequences of key events in adverse outcome pathways, or deviations from expected patterns of occurrence that might indicate alternative pathways, supporting also the collaboration with the AOP Cluster / development of AOP-Wiki 3.0; 5c. The next step will be enrichment of the putative AOPs with clinical / toxicological data and digital phenotyping. Inversely, the use case will explore whether AOP data could be used for healthcare tasks, e.g., differential diagnosis or supporting epidemiological analyses, as a means to bridge toxicological and medical datasets more effectively. 5d. A final step, through engagement with the breadth of PARC projects will be identification of demonstration adverse outcomes / diseases, whereby the workflow and tools developed will be benchmarked, documented and applied in complex real-word settings. A7.3.2 Methods for uncertainty characterisation, propagation and quantification as a basis for harmonisation in RA (Partner Involved: IISPV, ANSES, KWR, MU, WR) Following the initial conceptual design, planning, and primarily data collection in Y2, activities in Y3 will be detailed implementation of selected use cases. For their implementation and evaluation use cases identified in Y2 (still ongoing) for exposure, hazard, risk, health impact assessment, and IATAs in collaboration with WP4, WP5, and WP6, will further be refined and developed. Eventually relevant outcomes will be implemented in the PARC integrative model toolbox in collaboration with T8.3. This activity will focus on qualitative and quantitative estimation of uncertainties at the different steps of the domain specific process and methodological approaches used for uncertainty propagation. Domain specific use case groups have been selected and they will be working to define the scope of each use case study. The report will recommend promising methods for further evaluation and refinement if needed. [Partners involved: KWR, WR]. Following three use cases are currently implemented and will continue in Y3. 1. Assessment of uncertainty in PBK models of PFAS exposure in humans and reverse dosimetry (uncertainty in PFAS exposure) (Lead: MU, Partners involved: IISPV, WR) 2. Bioassay Trigger Value uncertainty (Lead: KWR, Partners involved: ANSES, IISPV), Trigger values are derived based on data of individually tested chemicals in a bioassay. Roughly, the lowest measured effect in a bioassay caused by a chemical with a nearhealth effect at that dose is taken as the trigger value. Above this value, an effect in a sample could in theory be induced by that chemical. In reality, many other chemicals can induce effects that are less harmful. Additionally, chemicals that induce a low effect in a bioassay may have health impacts in other endpoints than measured in the bioassay. This means that there is uncertainty in interpretation of the possible risks associated with a measured effect in a bioassay and the relation to the trigger value. The case will showcase methods to quantify these uncertainties. 3. Control Coefficient analysis of PBPK model (Lead: IISPV, Partners involved: TBD): Sensitivity coefficients quantify the effects of (small) changes in any parameter on any dependent variable, whereas a control coefficient quantifies the extent to which a catalytic/biochemical process determines a system variable. The objective of this use case is to develop the system biology approach that is called Metabolic Control Analysis (MCA) DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 97 for PBPK and investigate the control coefficients that are most relevant for a toxicokinetic system. The planning of these use cases has already started in Y2 and detailed implementation will continue in Y3. A7.3.3 Novel computational methods for integrating and extracting knowledge from nonstructured data Details per project: - P7.3.3.a_Y3_ ALT-IST_IISPV: Scoping study for tool development, challenges, and applications is completed. Methodological development started in year 2 will continue this year with the implementation in case study with WP 5.3 immunosuppression and adult neurotoxicity group. Text mining application for WP 6 will continue in year 3 as well. Tools developed during the scoping study will be released with articles. [Partners involved: IISPV (ES), UoB (UK), ANSES (FR), INSERM (FR), JSI (SI), AUTH (EL), MU (CZ), UL-LACDR (NL), KI (SE), NIVA (NO)] Specific actions for year 3 include: •Harmonization and integration of scoped text mining tools into a single platform to build a customized text mining tool. [Participants: IISPV, UoB] •Development of a harmonised FAIR evidence representation framework for computed entity associations. [Participants: UOB/IISPV] •Systematic evaluation of methods for deriving binary and typed relationships between biomedical / toxicological entities based on transactional occurrence data. [Participants: UOB/IISPV] •Exploration of methods for involvement of knowledge graphs in identification of entity associations from transactional occurrence data. [Participants: UOB/IISPV] •Mapping of other information source for integration. [Participants: UOB, IISPV] •Building a consistent data exchange schema according to FAIR principle to integrate and assemble information from wider sources. [Participants: IISPV, UoB] •Compiling data from mapped sources in the format of chosen schema for integration (especially in the context of the developed evidence metadata format). •Development of FAIR AOP in collaboration with WP 7.1 Use case 2 (Partners involved: UL-LACDR). Gene expression data is characterized by some accepted ontologies at the gene/protein level (e.g., NCBI Gene, UniProt, ..) and some at the pathway or functional levels (e.g., Gene Ontology, WikiPathways, ..). However, both levels are at the moment sub-optimal to inform risk assessment as they are either too detailed and not informative (gene level) or redundant and not pertinent to the toxicological experiments (pathway and functional level). Gene co-expression networks defined on the basis of exposure-derived experiment represent a good starting point to obtain data that is fitting the risk assessment domain and that achieve data dimensionality reduction, however the annotation of such co-expression networks is at the moment not standardized but expert-based and time consuming. In Y3 we will develop an automated ontology naming application, including additional data sources for genes or gene sets. These would include compound modulation and pathology information, using existing datasets (e.g., DisGeNET) and text mining on literature and clinical trials. The to-bedeveloped FAIR (connection to 7.2.4) ontology will be tailored for risk assessment use and will DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 98 link to the information sources used (provenance). The ontology terms with knowledge on the function of individual genes and interactions between genes/proteins within modules can then be compared to existing literature and data repositories using text mining tools. A7.3.4 Identify additional needs in PARC for innovative analyses and promising evolutions in the data science landscape, and translate them in use cases for evaluation The objective of this activity is to identify emerging needs in PARC for innovative analyses on one hand, and promising innovative techniques on the other hand. For the current annual plan, scoping study done in Y2 will continue. Based on this implementation planning will be executed with the steps mentioned below with collaborating partners. Use case 1 (7.3.4.a): Pharmacophore modelling using machine learning for screening Blood Brain Barrier (BBB) permeation of xenobiotics: This use case aims to investigate the effectiveness of different fingerprints generated based on pharmacophore modeling in deciphering the blood– brain barrier permeation of xenobiotics. With pharmacophore modeling, this study will explore the influence of the P-gp protein in the transportation process. Scoping and testing with limited data sources have been completed and the work is published (https://doi.org/10.3390/ijerph192013471 ). Data collection and further model testing started in year 2 will continue in year 3 with specific focus on identifies chemical groups in the PARC. [Partners involved: IISPV, UFZ, JSI] To achieve this objective, the use case will perform the following activities:  The collection of chemical data from reviewed literature sources and databases, followed by a filtering and standardization process to obtain a stabilized 3D structure.  A scaffold of the collected data will be generated to analyze the distribution of the core structure of the chemical responsible for permeability.  Stabilization and hydration of the protein retrieved from the protein data bank (PDB) will be undertaken, for docking purposes.  Different methods will be explored to generate pharmacophore fingerprints including receptor-based and ligand-based methods. The residue-based pharmacophore will be generated by docking the P-gp substrates and extracting the most common residues involved in the interaction. Whereas, the interaction-type pharmacophore will be generated using the docked chemical molecules, which will further be processed with the proLIF library to generate a 9-bit fingerprint and Rdkit.  The generated fingerprint and classical fingerprint will then be trained on a classical algorithm, such as Support Vector Machine (SVM), RF (Random Forest), and naïve Bayes, for comparison. New generation of ML method like graph model will also be implemented for methodological comparison. This use case has been developed in consultation with WP5 and WP8 and activity will be complemented with BBB experimental data generated in Task 5.3.4a (P5.3.4.a_Y1_PBK_Kinetics_Fraunhofer) and the computational tools for early warning system in Task 8.2. Use case 2: Scoping study of AI&ML-driven computational NAMs for use in NGRA: Activity 7.3.4 will also collaborate with A6.4.3 with a selected project P6.4.2.c_Y1_ NAMAM_UT: AI&ML-driven computational NAMs for use in NGRA lead by UT (EE) and work on landscaping DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 99 and readiness of NAMs based on advanced AI&ML approaches for use in chemical RA. This activity is a collaborative activity between two WPs and WP7.3 will support and provide input to the planned activity of A6.4.2. Here the focus is on the documentation of the data feeding into these models, and of the predictions coming out, and how to ensure transparency of these and their FAIRness. [Partners involved: UFZ, JSI, IISPV, ] Scoping studies and use cases performed in T7.3 will be reported in deliverable D7.4 1st Evaluation of innovative analytical approaches and uncertainty approaches for introduction in chemical RA. Deliverables D7.3 1st report on Data infrastructure, tools and services for FAIRification and reuse of chemical RA data (including P7.2.2.a_Y1_chemicals-in-environment_MU_VITO, M36; P7.2.2.b_Y1_HBMdatasets_VITO, M42) – Leader: VITO (M36) D7.4 1st Evaluation of innovative analytical approaches and uncertainty approaches for introduction in chemical RA (P7.3.3.a_Y1_ALT-IST_IISPV, M60) – Leader: UU-IRAS (M36). The leader of this deliverable is replaced by IISPV. Additional Deliverables: No additional deliverables – most WP7 activities in year 2 and year 3 will be reported in either D7.3 or D7.4. WP N° WP8 Lead Beneficiary AUTH/UNINA WP title Concepts and toolboxes Partner N° 1 1.1 1.4 3.3 4 4.6 8 10.2 12 13.1 14 15 20 20.3 20.4 20.6 25 25.4 25.7 Partner short name ANSES INSERM INERIS BNN VITO ISSeP MU DTU EEA SYKE TTL UBA ISS IRFM IUSS UNINA RIVM UL-LACDR WR PM/ partner 3.8 7.2 0.5 1.5 2 0.5 25.5 2.1 3.8 5.8 5.1 4 1 16.3 14.7 2.5 19.1 1.9 26.2 Partner N° 25.8 26.3 26.4 26.5 27.2 28 29.2 31.3 34.5 34.6 35.8 35.12 36 36.3 36.4 43 51 52 Partner short name WU-TOX NILU NIVA NMBU UG-PL FMUL DGS NIC IISPV INSST IVL UU AUTH NKUA UOC EMPA BUL Cefas-Defra DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 100 PM/ partner 0.9 2.7 1 0.3 4 1.7 1 12.7 5.2 2 8.2 6 71.5 7.1 6 12.5 1.7 0.7 Start M25 End M36 Objectives The overall goal of WP8 is to support the development and consolidation of concepts and tools for chemical risk assessment, also considering Safe and Sustainable by Design (SSbD) chemicals and materials and their operationalisation. The specific objectives of WP8 for year 3 are: o Task 8.1: Complete the V1.0 of the SSbD toolbox and assess its applicability through case studies o Task 8.2: Initiate the development of the PARC EWS and design a validation framework to support the EWS based on the completion of the identification framework o Task 8.3: Implement case studies for further mapping the needs of the PARC model network, based also on the inventory of models and tools and to deliver the first beta version of the PARC model network Description of Programmed Activities Task 8.1: Safe and sustainable by design (SSbD) Co-Leaders: RIVM (NL), EMPA (CH), AUTH (EL) Partners: INERIS (FR), BNN (AT), MU (CZ), DTU (DK), SYKE (FI), TTL (FI), UBA (DE), ISS (IT), IRFM (IT), IUSS (IT), UNINA (IT), NILU (NO), NMBU (NO), UG-PL (PL), FMUL (PT), NIC (SI), INSST (ES), IVL (SE), BUL (UK), Cefas-Defra (UK) A8.1.1. Translate EC SSbD criteria & methodology towards operationalisation In year 3, Activity 8.1.1 comprises two lines of action: (a) timely communication approach for dialogue between PARC 8.1 and the EC (RIVM, EMPA, AUTH), other PARC WPs (AUTH, INERIS, UBA) and outside PARC (RIVM, EMPA, IVL), with the HE WP21-22 and WP23-24 projects working on SSbD, and (b) advancing operationalization and non-technical support to the SSbD toolbox development. The focus of this year will be the further development and refinement of the translation of the SSbD framework for operationalization (AUTH, RIVM, EMPA, IVL) towards updating the PARC SSbD toolbox. We have conceptually linked chemical innovation with the EU SSbD assessment methodology so far. We will refine our approach by implementing a novel and comprehensive co-creation process with representatives of EC, industry, scientists and regulators in tandem with experience gained from the use cases (activity 8.1.3). We will also make a first step toward linking assessment and design aspects of the SSbD framework in terms of tools and processes (AUTH, EMPA, IVL, RIVM). The output of these activities will be 3 peer reviewed articles detailing the various technical and process aspects, decisions and pathways in the innovation based SSbD approach implemented in the PARC SSbD toolbox. This activity will provide inputs to the DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 101 PARC SSbD toolbox workflow development (activity 8.1.2) and additional case study implementation (activity 8.1.3). The work plan in year 3 includes the activities below:  Continued discussion and interaction with industry (RIVM, AUTH, EMPA, IVL, Unina, IUSS). A two-way communication with potential users through software development ensures that the innovation context and user needs are accurately captured, while garnering wider acceptance for SSbD framework and toolbox. Through implementing a bespoke interview and focus group approach, we have arrived at many insights on chemical innovation and the operationalization of SSbD. These will be further updated by the identification of user expectations and requirements for the SSbD toolbox (AUTH, EMPA, IUSS), including feedback of the toolbox experience from various user groups. As a follow up, we will develop a workshop to seek user feedback on the translation of the SSbD framework for operationalization, toolbox features, workflow, user interface and the case studies.  Regulators and risk assessors have vast experience in the application of safety assessment approaches and in the interpretation of results. In workshops we will interact with regulators and risk assessors to discuss the current developments in SSbD, the SSbD-toolbox and its possible uses. We will explore questions focused on the use of SSbD seen from a regulatory context, interpretation of SSbD-results in early development stages, and balancing the outcomes from a safety and sustainability point of view. The goal of the workshops is twofold: raising awareness on the topic of SSbD in the world of regulators and risk assessor and exploring questions and issues around early innovation/low TRL assessments (RIVM, AUTH, EMPA, IVL, Unina, IUSS).  The PARC consortium and the broader community have vast collective experience on safety and sustainability assessment methods. We will engage in in-depth technical discussions with various experts on various safety, sustainability, and socioeconomic assessment methods to further deepen the technical credibility of the toolbox and allowing incorporation of methods that can soon be implemented in the toolbox.  We shall build a collaboration scheme with newly funded projects under HE 2023-24 (in collaboration with WP3 and CT on synergies) in the chemical and nanomaterial domains (AUTH, RIVM). Moreover, new projects and their case studies could be invited to present their vision and goals in task 8.1 meetings and periodic project updates will be set up with a view to incorporate eventually novel methods/tools under development in these projects into the PARC SSbD toolbox. We shall collaborate with the IRISS project to this end. A8.1.2. Toolbox development Version 1.0 of the toolbox will be delivered in the end of year 3 (RIVM, EMPA, AUTH, BNN, MU, DTU, SYKE, IRFM, IUSS, UNINA, IVL) based (a) on the further experiences that will be obtained through the case studies performed in A8.1.3. and (b) from stakeholder input, with a particular focus on potential users of the toolbox (SMEs, industry etc). Additional state-of-the-art knowledge on developments and instruments applicable for exposure (WP4), hazard (WP5) and risk assessment (WP6) (RIVM, EMPA, AUTH, INERIS, ISS, IRFM, IUSS, UNINA, UG-PL, FMUL, NIC, INSST, IVL, BUL, Cefas-Defra) and sustainability assessment (AUTH, INERIS, BNN, MU, DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 102 DTU, SYKE, UBA, NILU, NMBU, NIC, INSST, IVL, BUL, EMPA) will be implemented. Additionally, the decision support approach will be further developed, incorporating various algorithms and tools to effectively support the multi criteria decision analysis (AUTH, EMPA, SYKE). The development of the toolbox will follow a concurrent engineering and iterative approach (AUTH, IUSS). Within Y3 (end of April 2025), version 1.0 of the SSbD toolbox will be completed (AUTH, IUSS, IVL, EMPA, IRFM, DTU, TTL, MU, RIVM), building on the current version 0.1 and further elaborating on the workflow of available tools for early and late innovation stages, with an emphasis on tools amenable for use by SMEs. Detailed actions regarding the toolbox development will include the further identification and adaptation of existing tools, either within the PARC consortium (MU, AUTH, IRFM, UG, DTU, BUL, IUSS, FMUL, TTL, NILU, ISS, INSST, NMBU, IVL, CEFAS-Defra, RIVM), or outside PARC (EMPA, RIVM, IUSS, UNINA, BNN), as well as the development of new tools, aiming to fill the implementation gaps that will be highlighted by the case studies. Particular attention will also be paid to specific modules updating user requirements and functional specifications of the SSbD toolbox to accommodate occupational safety and health aspects (TTL, UNINA, AUTH), that are critical for Step 2 of the SSbD framework. In addition, additional models for assimilating results of NAMs (and in particular omics), such as bioinformatics and systems biology models (AUTH) will be incorporated in the array of available models. It has also been made evident that the various tools to be included in the toolbox present vast differences among them regarding the programming language (Java, Python, acslxtreme, R) and user interface (web-based, software based). The solution to these technical obstacles will include the development of a docker container. The user interface will be web-based. In some cases (for specific tools) a client-side application may be needed, executed from the web browser's window that will guide the user through the SSbD toolbox. For authentication and authorization, we will strive for all PARC systems to have a single-sign-on (SSO). To this end, we consider Life Science Login (formerly ELIXIR AAI) as the most viable solution. Finallya very critical part of the workis the connection of the various tools on a technical level by developing workflow pipelines. For this purpose, linking the models will take stock of the input-output relationships that have been reviewed in Y2 and will be further explored through the case studies. Options to be developed, include the following elements:  A separate manual pipeline, in which the user places the individual tools in sequence while collecting and mapping the inputs/outputs during the process. The manual pipeline requires a way to export and input data obtained for and needed by the tools.  Automated pipelines will be developed; although this is a long-term development, efforts towards this direction will be initiated within the 3rd year of PARC. These pipelines might represent either a new “pipeline tool”, which could be a linking portal or dashboard or as a pipeline integrated in one of the existing tools. The automated pipeline requires that the tools have interfaces for automated running of the models. Efforts for the FAIRification of the SSbD toolbox will continue in Year 3 – in particular this willallow future models to be readily used within the same framework on the basis of a standardized input / output protocol, in relation to the ongoing work of the ontologies group in PARC. A critical part of the work regarding the successful operation of the toolbox, will be the link with various databases that will feed with data the models (AUTH, IUSS, RIVM, EMPA, IRFM). In this direction, additional collaboration efforts with WP7 will include the use of FAIRified data, while blockchain-based systems will promote secure data sharing initiatives, that are necessary for DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 103 industrial and SME users. Blockchain technology (or other equivalent options) also enables the tracking of data usage and reuse, providing evidence of the quality and reliability of the data while simultaneously ensuring the integrity of the data being analyzed. A summary of the timeline of the toolbox development activities is outlined in the following Gannt Chart Actions M25 M26 M27 M28 M29 M30 M31 M32 M33 M34 M35 M36 Development of MCDA module Inclusion of additional tools for chemical risk asessment Modules to assimilate NAMs Improved models for occupational exposure and health Link modelling tools outside PARC Additional models functionally linked using docker containers Develop pipelines for key safety assessment scenarios Continuous efforts for PARC toolbox FAIRification Development of blockchain-based system for data exchange Single-sign-on (SSO) autorisation system Update wizard A8.1.3. Towards operationalisation: Use case & indicators Version 0.1 of the PARC SSbD toolbox, implemented during year 3 according to the feedback from stakeholders and the added value gained in the bisphenols use case will further be operationalized and applied in additional use cases in the field of task 8.1.3. The aim of such activities will be to operationalize the integration of the toolbox benefitting from the experience gained in selected case studies (IVL, AUTH, IUSS, UBA, FMUL, UNINA, TTL, EEA, KI, BNN, Cefas-Defra, RIVM). User feedback on the PARC SSbD toolbox v.0.1 will be retrieved on the performance of the toolbox in the respective case studies in order to gain deep inside into requirements useful to expand simple tools during the process (IVL, AUTH, IUSS). In order to accelerate both the toolbox development, as well as the methodological contributions from other WPs, SSbD will be part of the cross-WPs bisphenols case study. Additional case studies will be used for the toolbox development. Selection will be based on several criteria decided and discussed under task 8.1.3 activities, with a view to cover many different aspects and application situations specifically considering conditions rich, intermediate and poor in data alternatives. The work in year 3 will allow to develop and monitor additional use cases and indicators, supporting the follow-up actions resulting from the conclusions of year 2, taking stock of the input received from various stakeholder interactions or formed in WP3 (AUTH, UBA, EEA). Additional use cases will take stock of the PARC internal 8.1.3 survey, already established connection with external projects (Mistra SafeChem) and newly established SSbD HE projects. Focus of the use case selection will be on the specific policy need from a safety/sustainability point of view, specific needs for further toolbox development and testing, and availability of user-based test networks. In addition, beyond diverse chemical families chemical products and mixtures will be considered as well. DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 104 The definition of case studies as possible settings for testing the toolbox, will be based on the inventory of candidate case studies compiled during year 1 and 2. This is a gross list based on a literature search, a questionnaire to stakeholders in 8.1, reach-out to associated projects also through an internal survey promoted during year 1, e.g. IRISS and the JRC cases, and also an outreach to other WPs in PARC to identify candidate chemicals. Use cases in year 3, will be helpful to more deeply define i) features that makes a tool useful in the context of SSbD, i.e. to determine what criteria should be used when evaluating the tools; ii) information required at each stage of SSbD; iii) endpoints useful in SSbD. According to an iterative approach, specific attention will be enforced to define workflow and involvement of tools for early and late innovation stages, with an emphasis to be used by SMEs. This plan will consider the barriers as well as incentives for implementation collated from stakeholders involved in the use cases (IVL, UBA, UNINA). Beyond aspects related to chemicals, materials and processes and how these result in safety and sustainability aspects, additional case study definition and execution will be planned, from the viewpoint of occupational safety and health (IVL, UNINA, TTL). During Y3, the inventory of relevant indicators to follow the progresses of sector applicability of the toolbox will be further evolved, accounting from the various interactions emerging from the Y2 experience within and outside PARC, including the indicator programme foreseen by EEA and in collaboration with Task 3.2. We are aiming for 3-5 cases for each of the steps in the SSbD procedure. As it will possibly be difficult to identify case studies that can help us test the toolbox for all steps, some case studies may only be possible for one or the other step. Specific actions will include: 1. Workshops to discuss and agree on case studies for the v.1.0 updated toolbox operationalization Reach out to shortlisted cases and set up meetings to discuss opportunities for collaboration around the cases. If relevant, define new cases beyond those compiled and try to find collaboration partners, inside and outside PARC. 2. Define the amount of information needed in the dry-run with use cases when moving from the EC framework stage 1-5 3. Define the indicators to be considered in the use cases, taking into account the inventory of indicators in the JRC framework and in the tools revised to prepare the version 1.0 of the toolbox 4. Decide on the final selection and establish agreements with the external stakeholders a. Establish working groups/task forces among the 8.1.3. stakeholders, related to each case study b. Each Task force defines a work plan for the work to be carried out, e.g. scope of work, what tools to test from 8.1.2, time plan, resources to be committed 5. Carry out the work including reporting back/exchanging experiences A8.1.4 Knowledge sharing & Education as key factors for efficient SSbD operationalization Building on the results of Year 2, work on the establishment of the knowledge sharing platform on SSbD will be continued (RIVM, BNN, SYKE, TTL, UBA, UNINA, NMBU, FMUL, NIC, INSST, AUTH). DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 111 training plan for Y3, as defined in AD9.1. o Provide the necessary logistical support to organizers of local training events. o Update PARC website to feature information on (external) existing training of potential interest to partners and stakeholders. Description of Programmed Activities Task 9.1: Laboratory networking Leader: ISCIII (ES) A9.1.1 Identify existing laboratory networks, draw up and maintain up-to-date and active a database of the laboratory networks Partners: NPHSL, SZU-SK, ANSES, AU, BPI, BRGM, CSIC, FISABIO, FMUL, INERIS, INSA, ISCIII, LNE, MU, NIPH, SCIENSANO, STAMI, FNS, VSCHT, GCSL, RSU, UK, ONIRIS To update the networks already created (HBM), a communication channel will be established through the PARC website. In this way we will track the inclusion of new laboratories as well as the update of information of those already included. The same approach will be applied for the catalogues for the different domains of interest already addressed in Y1 and Y2; air, indoor and water. Given the complexity of the domain articles/consumer products, their catalogues will be stepwise approached from Y3. In addition, we will start working on the environmental field of soil and sediment (postponed from Y2 to Y3) and food and feed. The first catalogues will be available by M36. The information collected from the laboratory networks (including name, contact, country and substances and matrices analyzed) will be translated into a more useful and attractive format. The interactive map developed and hosted in the PARC website during Y2 will be updated and improved in Y3. A9.1.2 Promote the development of new laboratory networks and support their consolidation Partners: FISABIO, INERIS, AU, BRGM, FMUL, INSA, ISCIII, MU, NPHSL, LNS, NIPH, SCIENSANO, ISSeP, FNS, VSCHT, GCSL, NMBU Based on the information of existing networks and their development status, experience, extension, etc. a detailed analysis will be done to identify the weak points that need to be improved/developed to achieve a better interaction among laboratories. Additionally, alternatives to the sustainability of the networks (out of research projects) will be explored. The list will serve as a living document and will be updated alongside the gradual creation of the networks. A9.1.3 Facilitate the coordination and linkage of existing and new laboratory networks Partners: CSIC, INERIS, BRGM, FMUL, INSA, LNE, MU, LNS, STAMI, ISCIII, ISSeP, FNS, VSCHT, GCSL, NMBU DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 112 Initial strategies and tools to achieve the coordination and linkage of the networks have been defined in Y2. During Y3, new strategies will be explored, and the first activities will be implemented (workshops, platform to exchange information, etc.). A9.1.4 Develop an interactive tool (dashboard) to show the capacities of the laboratory networks The information collected from the different laboratory networks will be included in a dashboard which will be part in the future of the PARC data hub developed in collaboration with Task 7.2 (ISCIII, GCSL, LNS, NMBU, FMUL). The concept, design and technical implementation of the dashboard have been established in Y2 in collaboration with Task 3.2, Task 7.2 and all the Task 9.1 partners. During Y3, the dashboard will be implemented on the PARC Data Hub/PARC webpage and will start running with the data collected in Y1-Y2. For the upcoming years, the dashboard will be fed continuously with updated information. Task 9.2: Building exposure monitoring capacities Leader: MU (CZ) A9.2.1 Mapping of exposure monitoring capacities Partners: ANSES, Inserm, Oniris, LNE, SpF, ISSeP, Sciensano, IMROH, MU, VSCHT, AU, NCPHP, NPHSL, LNS, UU-IRAS, STAMI, FMUL, INSA, ENSP, SZU-SK, CSIC, ISCIII, AUTH, BPI, GCSL Mapping of the existing biomonitoring and environmental exposure monitoring networks initiated in the first two years in a close collaboration with WP 4.1 and 4.2 will continue in Y3. Together with WP7.2 and Task 9.1, a tool presenting the outcomes of ongoing surveys will be developed as an important part of the PARC Data Hub. Specific attention will be paid to the harmonisation of parameters (such as biomarkers) collected across various surveys. Surveys mapping capacities (networks, projects, databases) potentially providing data on Y3 priorities (water, sediment) will continue to be distributed with the aim of developing their catalogues by M36. New effort will be directed on development of harmonised templates for such surveys. A9.2.2 Strengthening of exposure monitoring capacities Partners: ANSES, LNE, SpF, ISSeP, Sciensano, IMROH, MU, VSCHT, AU, LNS, UU-IRAS, FMUL, INSA, ENSP, JSI, CSIC, ISCIII, GCSL Joint development of PARC Data Hub with Task 9.1, WP7.2 and relevant WP4 partners will provide new tools not only for presenting data on existing biomonitoring and environmental monitoring networks, laboratories and databases but for assessment of gaps and future needs. This will provide a base for better targeting of research initiatives in WP4 but also for setting priorities and development of surveys in other WPs. Task 9.3: Joint activities – harmonisation DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 113 Leader: WR (NL) Partners: UNIVIE (AT), SCIENSANO (BE), MU (CZ), VSCHT (CZ), UBA (DE), RegionH (DK), AU (DK), CSIC (ES), ISCIII (ES), FNS (ES), INRAE (FR), ANSES (FR), BRGM (FR), INERIS (FR), LNE (FR), ONIRIS (FR), BPI (GR), GCSL (GR), LNS (LU), NIPH (NO), UNN (NO), STAMI (NO), NMBU (NO), INSA (PT), JSI (SI), NLZOH (SI) Transversal activity: Towards harmonised QA/QC in laboratory testing This activity focuses on quantitative confirmatory methods. Suspectand non-target screening and bioanalytical assays are dealt with in T4.3. Based on the inventories on QA/QC regarding sampling, chemical analysis, and toxicity testing/toxicokinetics studies, five working groups (see below) will draft guidance documents on various QA/QC parameters with focus on sample types and substances/techniques prioritised/used in Y3-Y4 of WP4 and WP5. In this, existing generic international standards (e.g. IUPAC, Eurachem, ISO/IEC 17025, OECD) and existing domainspecific protocols are taken into account, and serve as a basis for more dedicated protocols/ guidances (and where appropriate criteria) for laboratory tests performed in the frame of risk assessment. The guidance documents will be disseminated through PARC internal laboratory contact lists, and to the wider community/stakeholders via the PARC website and/or PARCopedia. On-line meetings foreseen in Y3: core group (WG co-leads) 2-3x, WG meetings (4-10 per WG), and T9.3 plenary 1-2x, possibly one in person. WG-1: Overarching QA/QC working group on Sampling. Includes: fit-for-purpose sampling, passive sampling, pretreatment, storage/stability, artifacts, uncertainty. Lead: AU, LNE. Partners: ANSES-LSAI PCPPA, ONIRIS, INERIS, BRGM, LNE, Sciensano, MU, AU, LNS, STAMI, NMBU, UNN, INSA, JSI, CSIC, ISCIII, FNS, BPI. WG-2: Overarching QA/QC working group on Performance criteria chemical analysis. Includes: limit of detection and quantification (LOD/LOQ), identification, trueness/precision criteria, calibration, validation, batch control, measurement uncertainty. Lead: MU. Partners: ANSES, INRAE, ONIRIS, INERIS, BRGM, LNE, UNIVIE, Sciensano, MU, VSCHT, RegionH, UBA, LNS, WR, NIPH, STAMI, NMBU, UNN, INSA, JSI, BPI, GCSL. WG-3: Overarching QA/QC working group on Assessment of interlab comparability chemical analysis. Includes: (evaluation of) protocols for proficiency testing (PT/ICI/EQUAS), small-scale interlab comparisons, catalogue for PT providers, catalogue (C)RMs. Lead: ANSES, LNE. Partners: ANSES, ONIRIS, INERIS, BRGM, LNE, Sciensano, MU, VSCHT, UBA, LNS, WR, NIPH, INSA, JSI, CSIC, ISCIII, BPI, GCSL. WG-4: Overarching QA/QC working group on Reporting and acceptability of results from chemical analysis. Includes: reporting requirements, normalisation or results, acceptability of lab data, criteria for qualification of labs. Lead: ONIRIS, LNS. Partners: ANSES, INRAE, ONIRIS, INERIS, BRGM, LNE, UNIVIE, Sciensano, MU, VSCHT, AU, UBA, LNS, WR, NIPH, NMBU, INSA, JSI, CSIC, BPI, GCSL. WG-5: QA/QC Effect directed assays (EDA), moved from T9.3 to T4.3) DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 114 WG-6: Overarching QA/QC working group on Toxicity testing & kinetic studies. Includes: in vivo and in vitro test systems (novel approach methods, NAMs), reporting. Lead: NIPH, STAMI. Partners: ANSES, INERIS, Sciensano, LNS, WR, NIPH, STAMI, NMBU, INSA, FNS. Task 9.4: Training Leader: INSA (PT) Partners: ANSES (FR), INRAE (FR), ONIRIS (FR), BRGM (FR), LNE (FR), UMIT (AT), Sciensano (BE), MU (CZ), VSCHT (CZ), IPA (DE), IRFM (IT), RSU (LV), NPHSL (LT), LNS (LU), STAMI (NO), NMBU (NO), ENSP (PT), UAVR (PT), JSI (SI), ULFFA (SI), NIJZ (SI), CSIC (ES), ISCIII (ES), FNS (ES), IMM-KI (SE), BPI (GR), GCSL (GR), UEF (FI) Building on data obtained in the training needs assessment survey (D9.3), a training plan has been developed (AD9.1) to cover the topics identified by partners and stakeholders. The plan includes four in-person training courses to be carried out in Y3 (1. FAIR data and databases; 2. Exposure Science and modelling; 3. Health Risk Assessment of Chemicals – principles and applications; and 4. Quality Assurance and Quality Control), under the scientific coordination of different PARC partners, namely JSI, Sl (courses 1 and 4), MU, CZ (course 2) and IMM-KI, SE (course 3) and aimed at both PARC partners and stakeholders. Additionally, a remote training course on in silico models, coordinated by IRFM, IT, is also planned for Y3. Supplementary training materials (e.g., a slide deck on new, non-invasive matrices) will also be made available. The local organizers of training events to be carried out under PARC will receive support from task 9.4 members, covering dissemination, registration, preparation and distribution of certificates, preparation, distribution of training evaluation surveys, and training evaluation assessment. In parallel, information on external training (outside PARC) on relevant topics (i.e.: FAIR & Databases; Human Health; Risk Assessment; Statistics & Modelling; Transferable Skills; Hazard Assessment; Exposure Assessment; Policy and Regulation) will be continuously updated on PARC website. Deliverables: D9.4: 1st Generic guidance documents for QA/QC on sampling; chemical analysis; toxicity, & toxicokinetics studies – Leader: WR (New delivery date M36)”. D9.5: Report on Training events Y2 – Leader: INSA (New delivery date M30) D9.6: Update 1 of the Generic guidance documents for QA/QC on sampling; chemical analysis; toxicity, & toxicokinetics studies – Leader: WR (M32), must be cancelled as the new delivery date for D9.4 is M36. D9.7 Laboratory catalogue and network platform (dashboard) Y3 – Leader: ISCIII (M36) D9.8 Catalogues on environmental and biomonitoring networks Y3 – Leader: MU (M36) D9.9 Report on Training events Y3 – Leader: INSA (M36) Additional Deliverables: NA DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 115 Table 2.2.b: AWP Set of Activities Activity No Activity Title Lead Participant No Short name of lead participant PersonMonths Start Month End month 1 Coordination and management 1 ANSES 249.4 25 36 2 A common science-policy agenda 3/12 EAA/EEA 179.1 25 36 3 Synergies, collaborations and awareness 29/36.2 INSA/GCSL 181.8 25 36 4 Monitoring and exposure 15/2 UBA/SpF 1652.1 25 36 5 Hazard Assessment 16/1 BfR/ANSES 1875.9 25 36 6 Innovation in regulatory risk assessment 25/35.7 RIVM/KEMI 1595.2 25 36 7 FAIR Data 4/59 VITO/UOB 286.9 25 36 8 Concepts and toolboxes 36/20.6 AUTH/UNINA 288.9 25 36 9 Building infrastructural and human capacities 34/8 ISCIII/MU 227.1 25 36 TOTAL 6536.4 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 116 Table 2.2.c: Additional Deliverables List WP AD N° AD name Lead participant Short name Type[1] Dissemination level[2] Delivery date Description WP2 AD2.1 Status report on NGRAroute BfR R PU Initial due date M24, postponed M29 The scope of this AD was changed from a "first draft high-level NGRAroute roadmap" to a "status report on NGRAroute". The main reason for the delay is that events regarding the COM roadmap have unfolded more slowly than originally anticipated. WP3 AD3.1 Report on risk communication activities EFET R PU M36 AD reporting the results of survey on risk communication. WP4 AD4.2 Periodic report on analytical methods and measurements for exposure and effect biomarkers ISCIII R PU Initial due date M12, postponed M36 AD related to P4.1.3.3.a_Y1_RoadmapLinkingHBMhealth_S pF_VITO, M52 WP4 AD4.3 Derivation of HBMGVs – first set UBA R PU Initial due date M12, postponed M36 AD related to P4.1.3.1.a_Y1_DerivationofHBM-GVs_UBA, M36 WP4 AD4.8 Report on the occupational exposure in general population surveys: analysis of existing data and TTL R PU Initial due date M18, postponed M29 AD related to P4.1.1.4.a_Y1_OccupFeasability_TTL, M29 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 117 WP AD N° AD name Lead participant Short name Type[1] Dissemination level[2] Delivery date Description recommendations for future general population studies WP4 AD4.9 Final report on the prioritization project AU/INERIS R PU M34 AD related to P4.2.b_Y2_MonitoringFrame_AU_INERIS, M30 WP4 AD4.10 Description of the study concept AU/INERIS R PU M36 AD related to P4.2.c_Y3_HumanExposure_INERIS_AU, M60 WP4 AD4.11 Progress report statistical analyses VITO R PU M36 AD related to P4.1.4.2.a_Y1_DataAnalysisHBM4EU_VITO, M36 WP6 AD6.7 Technical report outlining the regulatory needs for ERA development areas KEMI R PU Initial due date M24, postponed M36 AD related to P6.4.4.a_Y1_CRNCS1_KEMI, M42 WP6 AD6.9 Report on draft IATAs and associated case studies UL-LACDR R PU Initial due date M24, postponed M30 AD related to P6.1.1.a_Y1_HumanRelevance_RIVM, M36; P6.1.1.b_Y1_IATA_ED_UAntwerpen, M36; P6.1.1.c_Y1_IATA_GENTOX_Sciensano, M36; P6.1.1.d_Y1_IATA_STOT_UL-LACDR, M36 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 118 WP AD N° AD name Lead participant Short name Type[1] Dissemination level[2] Delivery date Description WP6 AD6.14 Report on current screening and enforcement structures TUKES R PU Initial due date M24, postponed M28 AD related to P6.4.3.a_Y1_SuProM_MU, M36 WP6 AD6.15 Report on existing database structures with recommended structures MU R PU Initial due date M24, postponed M36 AD related to P6.4.3.a_Y1_SuProM_MU, M36 WP6 AD6.16 Status of integration and use of NAMs in the EU chemical regulatory risk assessment landscape – a mapping exercise and gaps & needs analysis UNIBAS R PU Initial due date M24, postponed M36 AD related to P6.4.2.a_Y1_LandscapingSurv_UNIBA, M36; P6.4.2.b_Y1_NGRApractice_VKM_NIPH, M36; P6.4.2.c_Y1_NAMAM_UT, M36 WP6 AD6.195 Technical report informing on factors and processes needed to be included in the ERA to obtain an improved balance between reduced complexity and UFZ R PU M36 AD related to P6.4.4.c_Y1_ PPPEFF CS3_UFZ, M36 5 AD6.17 (Optimizing regulatory risk assessment and management of chemical mixtures in Europe) and AD6.18 (Dealing with mixtures in regulatory risk assessment through the use of monitoring data and NAMs) will be postponed from M36 to M40 due to the delay of the projects P6.4.1.a_Y1_OPREMIXCS1_BRUNEL_UGot and P6.4.1.b_Y1_MONAMMIXCS2_UFZ, delayed from M36 to M40. DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 119 WP AD N° AD name Lead participant Short name Type[1] Dissemination level[2] Delivery date Description increased ecological realism WP6 AD6.20 Technical report on factors and processes needed to be included in robust aquatic exposure predictions for regulatory use, including an assessment of geographic representativeness UFZ R PU M36 AD related to P6.4.4.b_Y1_PPPEXPCS2_SLU WP8 AD8.5 Update of the conceptual design of the SSbD toolbox based on stakeholder input and experience from the use cases and completion of the version 1.0 of the SSbD toolbox AUTh R PU M36 _ DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 120 2.3 Resources to be committed Table 2.3.a: Summary effort table WP1 WP2 WP3 WP4 WP5 WP6 WP7 WP8 WP9 Total PMs per partner 1-ANSES 124,5 12,0 1,0 54,9 75,2 78,0 24,7 3,8 0,9 374,9 1.1INSERM 1,0 4,5 0,0 7,1 197,4 13,2 3,1 7,2 3,0 236,5 1.2INRAE 0,8 0,0 0,0 85,3 70,4 33,9 0,0 0,0 2,1 192,4 1.3-CEA 0,0 0,0 0,0 11,9 0,0 0,0 0,0 0,0 0,0 11,9 1.4INERIS 0,8 0,0 0,0 12,8 8,4 2,0 0,0 0,5 2,1 26,6 1.5CNRS 0,0 0,0 0,0 2,8 23,0 0,0 0,0 0,0 0,0 25,8 1.6-INRS 0,0 0,0 0,0 14,8 12,6 3,0 1,5 0,0 0,0 31,9 1.7ONIRIS 0,0 0,0 0,0 17,6 0,0 10,3 0,0 0,0 1,3 29,3 1.8-IRSN 0,0 0,0 0,0 0,0 2,0 5,5 0,0 0,0 0,0 7,5 1.9-OFB 0,0 0,0 0,0 1,0 0,0 14,5 0,0 0,0 0,0 15,5 1.10BRGM 0,0 0,0 0,0 15,3 0,0 0,0 7,5 0,0 3,8 26,6 1.11-LNE 0,0 0,0 0,0 0,3 0,0 0,0 0,0 0,0 3,9 4,2 1.12CSTB 0,0 0,0 0,0 11,2 0,0 0,0 0,0 0,0 0,0 11,2 1.13EHESP 4,0 0,0 0,0 16,4 0,0 0,5 0,0 0,0 0,0 20,9 2-SpF 7,4 3,0 0,5 80,4 0,0 0,0 0,0 0,0 3,0 94,4 3-EAA 5,5 3,5 4,0 6,5 0,0 3,0 0,0 0,0 0,0 22,5 3.1AGES 0,6 0,0 2,0 0,0 0,0 17,3 0,0 0,0 0,0 19,8 3.2-AIT 0,0 0,0 0,0 0,0 12,0 0,0 0,0 0,0 0,0 12,0 3.3-BNN 0,0 0,0 0,0 0,0 0,0 0,0 0,0 1,5 0,0 1,5 3.4-MUI 0,0 0,0 0,0 31,2 21,6 3,0 0,0 0,0 0,0 55,8 3.5-MUW 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 127 WP1 WP2 WP3 WP4 WP5 WP6 WP7 WP8 WP9 Total PMs per partner 35.2-KI 0,0 0,0 0,0 0,0 1,0 8,8 0,5 0,0 2,0 12,3 35.3ULUND 0,0 0,0 0,0 4,4 0,0 2,0 0,0 0,0 0,0 6,3 35.4ORU 0,0 0,0 0,0 11,9 0,0 3,0 0,0 0,0 0,0 14,9 35.5RISE 0,0 0,0 0,0 0,0 0,0 16,6 0,0 0,0 0,0 16,6 35.6-SU 0,6 0,0 0,0 8,5 6,5 46,0 0,0 0,0 0,0 61,6 35.7KEMI 3,4 0,0 1,0 0,0 0,0 17,3 0,0 0,0 0,0 21,7 35.8-IVL 0,2 0,0 0,0 11,4 0,0 9,2 0,0 8,2 0,0 29,0 35.9-SLV 1,0 0,0 0,5 0,0 0,0 0,0 0,0 0,0 0,0 1,5 35.10SLU 0,0 0,0 0,0 17,0 34,0 22,1 0,0 0,0 0,0 73,1 35.11UMU 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 35.12-UU 0,0 0,0 0,0 0,0 16,0 0,0 5,0 6,0 0,0 27,0 36-AUTH 5,6 29,0 10,0 16,0 21,0 43,0 7,0 71,5 3,2 202,3 36.1EFET 0,0 0,0 5,5 1,9 0,0 0,0 0,0 0,0 0,0 7,4 36.2GCSL 3,0 5,0 19,0 1,0 0,0 0,0 0,0 0,0 3,1 31,1 36.3NKUA 0,0 0,0 11,2 35,5 0,0 0,0 0,0 7,1 0,0 53,8 36.4UOC 0,0 0,0 3,9 0,0 0,0 0,0 0,0 6,0 0,0 9,9 37-BPI 0,6 0,0 2,5 15,0 46,1 40,5 0,0 0,0 3,5 108,1 38-FOPH 0,0 0,0 0,5 1,0 0,0 1,0 0,0 0,0 0,0 2,5 39AGROSC OPE 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 40UNISANT E 0,0 0,0 0,0 6,3 0,0 14,0 0,0 0,0 0,0 20,3 41EAWAG 0,0 0,0 0,0 26,5 23,0 10,8 0,0 0,0 0,0 60,3 42-ETHZ 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 128 WP1 WP2 WP3 WP4 WP5 WP6 WP7 WP8 WP9 Total PMs per partner 43-EMPA 0,0 0,0 0,0 0,0 0,0 0,0 0,0 12,5 0,0 12,5 44-FOEN 0,0 0,0 0,0 0,0 0,0 5,0 0,0 0,0 0,0 5,0 45-USI 0,0 0,0 0,0 6,2 0,0 2,0 0,0 0,0 0,0 8,2 46UNIBAS 0,0 0,0 0,0 0,0 0,0 23,0 0,0 0,0 0,0 23,0 47-SECO 0,0 0,0 0,0 0,4 0,0 0,0 0,0 0,0 0,0 0,4 48-ECHA 0,0 24,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 24,0 49-EFSA 0,0 5,0 0,0 0,0 0,0 4,1 2,0 0,0 0,0 11,1 50UKHSA 2,0 0,0 2,0 3,5 0,0 0,0 0,0 0,0 1,0 8,5 51-BUL 0,0 0,0 0,0 0,0 0,0 0,0 0,0 1,7 0,0 1,7 52CefasDefra 0,0 1,0 0,0 0,0 0,0 0,0 0,0 0,7 0,0 1,7 53UKCEH 0,0 0,0 0,0 5,0 0,0 10,1 0,0 0,0 0,0 15,1 54-EA 0,0 0,0 0,0 1,5 0,5 0,4 0,0 0,0 0,0 2,4 55-HSE 0,0 0,0 0,0 5,0 0,0 0,0 0,0 0,0 0,0 5,0 56-IOM 0,0 0,0 0,0 1,1 0,0 0,0 0,0 0,0 0,0 1,1 57-UBAH 0,0 0,0 0,0 3,0 0,0 0,0 0,0 0,0 0,0 3,0 58UNIABD N 0,0 0,0 0,0 0,5 0,2 0,0 0,0 0,0 0,0 0,7 59-UOB 3,0 9,0 1,0 0,0 18,0 26,5 5,0 0,0 0,0 62,5 60-UCL 0,0 0,0 0,0 0,0 0,0 2,0 0,0 0,0 0,0 2,0 61-EPA 1,2 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 1,2 Total PMs 249,4 179,1 181,8 1652,1 1875,9 1595,2 286,9 288,9 227,1 6536,4 Table 2.3.b: Other major cost items (travel, equipment, infrastructure, goods and services) 1 - ANSES Cost (€) Justification Equipment 66 000 Equipment costs for a confocal microscope as part of P5.2.1.a_Y1 Remaining purchase costs (<15% of pers. Costs) 323 878 Total 389 878 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 129 1.3 - CEA Cost (€) Justification Other Goods, Works & Services 10 400 Consumables as part of project P4.3.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 6 760 Total 17 160 1.4 - INERIS Cost (€) Justification Other Goods, Works & Services 20 318 Cellular models, test items, cell culture consumables (medium, flasks) of P5.3.4.a_Y1 (20 318€) Remaining purchase costs (<15% of pers. Costs) 17 995 Total 38 313 1.5 - CNRS Cost (€) Justification Travel and subsistence 1 660 Travel and subsistence for 1 person to attend 1 consortium meeting as part of Task 1.1 (830€) and 1 meeting as part of project P4.3.4.a_Y2 (830€) Remaining purchase costs (<15% of pers. Costs) 28 990 Total 30 650 1.6 - INRS Cost (€) Justification Other Goods, Works & Services 21 000 Laboratory consumables including for HMRS analysis and other goods as part of projects P4.1.1.4.c_Y1, P4.3.1.b_Y1, P4.3.1.d_Y1, P4.3.2.b_Y2, and P6.2.1.b_Y1 Remaining purchase costs (<15% of pers. Costs) 31 730 Total 52 730 1.7 - ONIRIS Cost (€) Justification Other Goods, Works & Services 10 000 Consumables as part of projects P4.3.3.b_Y2 and P4.3.4.a_Y2 Remaining purchase costs (<15% of pers. Costs) 20 440 Total 30 440 1.9 - OFB Cost (€) Justification Travel and subsistence 16 200 Travel and subsistence as part of P6.4.4.e_Y1 Remaining purchase costs (<15% of pers. Costs) 0 Total 16 200 3 - EAA Cost (€) Justification Other Goods, Works & Services 8 940 Consumables as part of project P4.1.1.2.a_Y1 (HBM survey) Remaining purchase costs (<15% of pers. Costs) 22 090 Total 31 030 3.2 - AIT Cost (€) Justification Other Goods, Works & Services 38 520 As part of project P5.2.1.e_Y1 : Consumables for stem cell media, growth factors, coating reagents, HPLC analysis, antibodies, qPCR, highthroughput qPCR chips, Western blot reagents, DNA-methylation EPIC DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 130 arrays, cell culture plastics, spheroid chips ; and use of large research infrastructure Remaining purchase costs (<15% of pers. Costs) 2 420 Total 40 940 3.4 - MUI Cost (€) Justification Other Goods, Works & Services 60 335 Consumables as part of projects P4.3.1.d, P4.3.2.c_Y3 and P5.2.1.d_Y1 Remaining purchase costs (<15% of pers. Costs) 50 160 Total 110 495 3.6 – UG-AT Cost (€) Justification Other Goods, Works & Services 4 600 Chemical consumables for analysis as part of project P4.3.3.b_Y2 Remaining purchase costs (<15% of pers. Costs) 2 330 Total 6 930 3.8 - UMIT Cost (€) Justification Other Goods, Works & Services 25 000 Meeting organisation costs for the Consortium meeting in May 2024 including Stakeholder Forum, International Board, and Governing Board Remaining purchase costs (<15% of pers. Costs) 1 660 Total 26 660 3.9UNIVIE Cost (€) Justification Other Goods, Works & Services 10 000 Consumables for project P4.3.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 50 600 Total 60 600 4.7 - UAntwerpen Cost (€) Justification Other Goods, Works & Services 43 569 Chemicals, purchase and maintenance of zebrafish transgenic lines, plastic consumables for zebrafish embryo exposures, kits and products for molecular and biochemical analyses, consumables for zebrafish housing, maintenance of zebrafish housing as part of projects P5.1.2.b_Y1, P5.2.1.b_Y1, P5.2.1.c_Y1 (41 569€) Consumables for LC-MS analysis as part of project P4.2.c_Y3 (2 000€) Remaining purchase costs (<15% of pers. Costs) 43 569 Total 86 986 5.2 – EV-ILVO Cost (€) Justification Other Goods, Works & Services 1 375 Consumables and reagents for P4.3.1.b_Y1 and P4.3.4.a_Y2 Travel and subsistence 500 Travel and subsistence as part of P4.3.4.a_Y2 Remaining purchase costs (<15% of pers. Costs) 2 950 Total 4 825 5.3 - VUB Cost (€) Justification Other Goods, Works & Services 30 000 Running costs and consumables related to experiments in project P6.1.1.c_Y1 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 131 Remaining purchase costs (<15% of pers. Costs) 32 750 Total 62 750 6 - CIPH Cost (€) Justification Travel and subsistence 1 660 Travel and subsistence for 1 person to attend GSB and NHCP meetings Remaining purchase costs (<15% of pers. Costs) 1 060 Total 2 720 6.1 - IMROH Cost (€) Justification Travel and subsistence 6 780 Travel and subsistence for: - 1 person to attend 1 meeting in WP1 - 2 persons to attend 2 meetings in WP6 - 2 persons to attend 1 meeting in WP7 - 1 person to attend 2 meetings in WP9 Remaining purchase costs (<15% of pers. Costs) 830 Total 7 610 7 – MOH-CY / SGL Cost (€) Justification Other Goods, Works & Services 41 000 Consumables and costs for analysis as part of HBM surveys as part of task 4.1 and P4.1.1.2.a_Y1 Consumables for P4.2.C_Y3 and P6.2.3.a_Y1 Remaining purchase costs (<15% of pers. Costs) 10 920 Total 51 920 8.1 – SZU-CZ Cost (€) Justification Other Goods, Works & Services 10 000 Consumables and costs for analysis as part of HBM survey in project P4.1.1.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 2 720 Total 12 720 8.2 - VSCHT Cost (€) Justification Other Goods, Works & Services 9 170 Consumables and chemicals, including consumables for LC-MS and GCMS as part of projects P4.2.c_Y3, P4.3.2.c_Y3, and P4.3.4.a_Y2 Travel and subsistence 2 490 Travel and subsistence for 1 person to attend 3 meetings as part of WP9 Remaining purchase costs (<15% of pers. Costs) 7660 Total 19 320 8.4 - JU Cost (€) Justification Travel and subsistence 3 320 Travel and subsistence for 1 person to attend 2 meetings as part of project P4.3.3.a_Y1 (1 660€), for 1 person to attend 1 meeting for task 4.1 (830€), and for 1 person to attend 1 meeting for WP1 (830€) Other Goods, Works & Services 2 575 Consumables for analysis as part of projects P4.3.3.a_Y1 and P4.3.3.b_Y2 Remaining purchase costs (<15% of pers. Costs) - Total 5 895 9 - UZIS Cost (€) Justification Travel and subsistence 2 622 Travel and subsistence for 1 person to attend 2 consortium meetings in WP7 (1 422€) and for 1 person to attend 2 National Hub Contact Points meetings in WP1 (1 200€) DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 132 Remaining purchase costs (<15% of pers. Costs) - Total 2 622 10.1 - AU Cost (€) Justification Other Goods, Works & Services 5 000 Consumables and laboratory materials as part of project P5.3.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 68 455 Total 73 455 10.4 - UCPH Cost (€) Justification Other Goods, Works & Services 35 500 Consumables and materials for LC-MS analyses (7 500€), SFC-MS analyses (5 000€), GCxGC-MS analyses (10 000€), high throughput ecotox analyses (5 000€) as part of project P4.3.3.a_Y1 Skin cell model with human keratinocytes and human fibroblasts as part of project P6.4.1.c_Y3 (8 000€) Remaining purchase costs (<15% of pers. Costs) 15 490 Total 50 990 11 - HB Cost (€) Justification Travel and subsistence 1 060 Travel an subsistence for 1 person to attend to 1 meeting in WP1 Remaining purchase costs (<15% of pers. Costs) 830 Total 1 890 13 - THL Cost (€) Justification Travel and subsistence 1 060 Travel and subsistence for 1 person to attend 1 meeting in WP1 Remaining purchase costs (<15% of pers. Costs) - Total 1 060 13.1 - SYKE Cost (€) Justification Other Goods, Works & Services 7 500 Costs for analyses as part of project P4.2.1.b_Y2 Remaining purchase costs (<15% of pers. Costs) 13 730 Total 21 230 14 - TTL Cost (€) Justification Other Goods, Works & Services 2 000 Consumables and other chemicals as part of project P4.3.2.b_Y2 Remaining purchase costs (<15% of pers. Costs) 44 680 Total 46 680 14.1 - FFA Cost (€) Justification Other Goods, Works & Services 1 000 Publications costs related to task 4.1 Remaining purchase costs (<15% of pers. Costs) 5 183 Total 6 183 14.2 - Tukes Cost (€) Justification Travel and subsistence 2 400 Travel and subsistence for 1 person to attend 2 meeting as part of project P6.4.3.a_Y1 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 133 Remaining purchase costs (<15% of pers. Costs) 2 830 Total 5 230 15.6 - KUM Cost (€) Justification Other Goods, Works & Services 10 000 Lab chemicals, tips, tubes, microsampling devices (VAMS, DBS), Instrument consumables (argon, sample cups), etc. related to project P4.3.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 4 320 Total 14 320 16.1 - Fraunhofer Cost (€) Justification Other Goods, Works & Services 24 000 Consumables for analyses as part of projects P4.2.1.b_Y2 and P5.1.1.a_Y1 Remaining purchase costs (<15% of pers. Costs) 29 225 Total 52 395 16.2 - KIT Cost (€) Justification Other Goods, Works & Services 7 500 Consumables for project P5.3.1.a_Y1 Remaining purchase costs (<15% of pers. Costs) 9 330 Total 16 830 16.3 - IUF Cost (€) Justification Other Goods, Works & Services 40 000 Consumables for project P5.2.1.e_Y1 Remaining purchase costs (<15% of pers. Costs) 43 780 Total 83 780 16.4 - IfADO Cost (€) Justification Other Goods, Works & Services 12 000 Consumables for project P5.2.1.b_Y1 Remaining purchase costs (<15% of pers. Costs) 12 830 Total 24 830 16.8 - UKON Cost (€) Justification Other Goods, Works & Services 25 700 Consumables for project P5.2.1.e_Y1: reagents for toxicological test and reagents for cell culture (hPSC) Remaining purchase costs (<15% of pers. Costs) 1 890 Total 22 720 16.9 - TiHo Cost (€) Justification Other Goods, Works & Services 20 000 Consumables for project P5.2.1.e_Y1: Cell culture medium for stem cell culture, Cell culture plasic ware, cell culture medium additives, antibodies, chemicals Remaining purchase costs (<15% of pers. Costs) 1 890 Total 21 890 17 - NCPHP Cost (€) Justification Other Goods, Works & Services 84 264 Reagents, consumables, kits, cell culture as part of project P5.2.1.d_Y1 and consumables for sampling as part of project P4.1.1.2.a_Y1 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 134 Remaining purchase costs (<15% of pers. Costs) 20 477 Total 104 741 18 - UI Cost (€) Justification Travel and subsistence 21 412 Consumables and costs for analysis as part of HBM survey in project P4.1.1.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 11 065 Total 32 477 19 - MOH Cost (€) Justification Other Goods, Works & Services 10 706 Consumables and costs for analysis as part of HBM survey in project P4.1.1.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 2 120 Total 12 826 20 - ISS Cost (€) Justification Other Goods, Works & Services 45 000 Consumables related to project P4.2.1.a_Y1 Remaining purchase costs (<15% of pers. Costs) 53 550 Total 98 550 20.5 - UMIL Cost (€) Justification Other Goods, Works & Services 20 381 Consumables for project P5.1.1.b_Y1: Chemicals, antibodies, ELISA kits, cell culture medium and supplements, buffy coats, etc Remaining purchase costs (<15% of pers. Costs) 18 613 Total 38 994 20.6 – DPH-UNINA Cost (€) Justification Other Goods, Works & Services 5 357 Publications costs as WP8 co-leader Travel and subsistence 2 950 Travel and subsistence costs for 1 person to attend 4 meetings in WP1 Remaining purchase costs (<15% of pers. Costs) 2 490 Total 10 797 21 - RSU Cost (€) Justification Other Goods, Works & Services 48 690 Consumables and costs for analysis as part of HBM survey in project P4.1.1.2.a_Y1 (34 940€) Consumables for sample collection and storage of biological and industrial hygiene samples as part of project P4.1.1.4.c_Y1 (10 750€) Publications fees as part of project P6.3.2.a_Y1 (3 000€) Remaining purchase costs (<15% of pers. Costs) 20 176 Total 70 406 21.1 - UL Cost (€) Justification Other Goods, Works & Services 4690 Consumables (reagents, tubes, micropipette tips, microfilters) as part of project P4.2.1.a_Y1 and P4.2.c_Y3 Travel and subsistence 2 180 Travel and subsistence for 1 person to 1 meeting for project P4.3.3.a_Y1 and P4.2.c_Y3 Remaining purchase costs (<15% of pers. Costs) 2990 DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 135 Total 9860 22 - NPHSL Cost (€) Justification Travel and subsistence 6 500 Travel and subsistence for 1 person to attend 6 meetings in WP9 and for 1 person to attend 1 meeting in WP1 Remaining purchase costs (<15% of pers. Costs) 2 720 Total 9 220 23 - LSMU Cost (€) Justification Equipment 10 000 Equipment costs for muffle furnace for project P4.1.1.2.a_Y1 Other Goods, Works & Services 2 000 Consumables and costs for analysis as part of HBM survey in project P4.1.1.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 6 610 Total 18 610 24.1 - LIH Cost (€) Justification Other Goods, Works & Services 11 367 Consumables related to project P5.1.1.b_Y1 Remaining purchase costs (<15% of pers. Costs) 20 000 Total 31 367 25 - RIVM Cost (€) Justification Other Goods, Works & Services 30 000 Consumables for project P6.1.1.b_Y1 (30 000€) Remaining purchase costs (<15% of pers. Costs) 108 020 Total 138 020 25.4 – UL-LACDR Cost (€) Justification Equipment 100 000 Costs for microscopy, culture facility, flow cytometry, sequencing for projects P5.2.1.a_Y1 (37 500€), P5.3.1.a_Y1 (15 000€), P6.1.1.c_Y1 (23 750€) and P6.1.1.d_Y1 (23 750€) Other Goods, Works & Services 69 250 Costs for Cell culture, molecular biology, microscopy, transcriptomics, chemicals, disposables, plastics for projects P5.2.1.a_Y1 and P6.1.1.c_Y1 Remaining purchase costs (<15% of pers. Costs) 69 560 Total 238 810 25.7 - WR Cost (€) Justification Other Goods, Works & Services 30 940 Consumables for project P4.3.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 74 976 Total 105 916 25.9 - SRU Cost (€) Justification Other Goods, Works & Services 5 625 Materials and consumables for collection and storage of biological and industrial hygiene samples as part of project P4.1.1.4.c_Y1 Remaining purchase costs (<15% of pers. Costs) 22 315 Total 27 940 26 - NIPH Cost (€) Justification Other Goods, Works & Services 139 500 Consumables such as natural toxins and kits, RNA seq kits, panel of antibodies for project P5.1.1.c_Y3 (45 000€), P5.2.1.e_Y1 (40 000€), P5.2.1.d_Y1 (25 000€), and P5.1.1.a_Y1 (15 000€) DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 136 Publication costs for P6.4.2.b_Y1 and P6.2.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 153 875 Total 293 375 26.2 - STAMI Cost (€) Justification Other Goods, Works & Services 22 500 Lab consumables as part of project P5.1.1.a_Y1 and P6.1.1.a_Y1 Remaining purchase costs (<15% of pers. Costs) 80 610 Total 103 110 26.5 - NMBU Cost (€) Justification Other Goods, Works & Services 46 000 Costs for analyses as part of project P5.2.1.e_Y1 Remaining purchase costs (<15% of pers. Costs) 12 330 Total 58 330 27 - NIOM Cost (€) Justification Other Goods, Works & Services 21 412 Consumables and costs for analysis as part of HBM survey in project P4.1.1.2.a_Y1 Remaining purchase costs (<15% of pers. Costs) 30 532 Total 51 944 27.1 – IEP-NRI Cost (€) Justification Other Goods, Works & Services 22 860 Costs for laboratory materials, reagents and services as part of WP5 including project P5.1.2.b_Y1 (18 940€) Conference fees and publications costs as part of WP6 including project P6.4.4.e_Y1 (3 920€) Remaining purchase costs (<15% of pers. Costs) 10 420 Total 33 280 27.2 – UG-PL Cost (€) Justification Other Goods, Works & Services 15 150 Purchase of reagents, organisms for biotests, analytical standards of investigated chemicals, laboratory accessories such as e. g. pipte tips, well plates and microplates for (eco)tocixological tests or other usable laboratory accessories for projects P4.2.a_Y1, P4.3.3.a_Y1 and P5.1.2.b_Y1 Remaining purchase costs (<15% of pers. Costs) 18 555 Total 33 705 27.3 – WULS-SGGW Cost (€) Justification Other Goods, Works & Services 62 190 Consumables and standards, solvents, reagents, services for projects P4.1.1.4.d, P4.3.1.b_Y1, P4.3.2.b_Y2, and P4.3.3.a_Y1 Remaining purchase costs (<15% of pers. Costs) 5 010 Total 67 200 28 - FMUL Cost (€) Justification Travel and subsistence 4 010 Travel and subsistence for: - 1 person to attend 1 meetings in WP1 (1 060€) - 1 person to attend 2 meetings in WP2 (2 120€) - 1 person to attend 1 meeting in WP8 (830€) DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 143 Transversal activities 2 036 066,27 12,68% 13 377 700,68 11,33% Task 4.1 1 692 043,46 € 10,54% 10 925 832,20 € 9,25% Task 4.2 289 680,12 € 1,80% 2 033 472,68 € 1,72% Task 4.3 54 342,70 € 0,34% 418 395,81 € 0,35% TOTAL WP4 16 058 203,94 100,00% 60 991 569,24 118 124 452,00 51,63% DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 144 Work Package 5 Task/Project ID Budget allocated for Y3 % Budget allocated for Y3 / total WP budget allocated for Y3 Total Budget allocated Total WP budget at proposal stage % Project Total Budget allocated / Total WP budget at proposal Projects 15 545 250,54 92,14% 50 255 335,26 52,02% P5.1.1.a_Y1 1 589 442,70 9,42% 4 984 130,17 5,16% P5.1.1.b_Y1 1 057 087,99 6,27% 3 562 262,66 3,69% P5.1.1.c_Y3 638 666,59 3,79% 1 312 322,21 1,36% P5.1.2.a_Y1 173 479,38 1,03% 501 413,84 0,52% P5.1.2.b_Y1 2 409 221,84 14,28% 8 108 156,77 8,39% P5.2.1.a_Y1 1 596 779,88 9,46% 6 181 076,19 6,40% P5.2.1.b_Y1 690 824,79 4,09% 2 316 391,83 2,40% P5.2.1.c_Y1 1 086 665,76 6,44% 3 425 417,26 3,55% P5.2.1.d_Y1 1 687 059,91 10,00% 5 260 680,94 5,45% P5.2.1.e_Y1 1 600 576,29 9,49% 4 803 408,96 4,97% P5.3.1.a_Y1 958 816,63 5,68% 3 302 200,10 3,42% P5.3.2.a_Y1 975 121,93 5,78% 3 315 845,04 3,43% P5.3.4.a_Y1 1 081 506,87 6,41% 3 182 029,30 3,29% Transversal activities 1 326 812,20 7,86% 9 583 689,11 9,92% Task 5.1 500 394,25 2,97% 3 627 370,98 3,75% Task 5.2 540 775,17 3,21% 3 812 017,87 3,95% Task 5.3 285 642,77 1,69% 2 144 300,26 2,22% TOTAL WP5 16 872 062,74 100,00% 59 839 024,37 96 602 616,00 61,94% DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 145 Work Package 6 Task/Project ID Budget allocated for Y3 % Budget allocated for Y3 / total WP budget allocated for Y3 Total Budget allocated Total WP budget at proposal stage % Project Total Budget allocated / Total WP budget at proposal Projects 12 470 896,29 93,74% 42 366 106,94 57,74% P6.1.1.a_Y1 395 291,75 2,97% 1 184 329,66 1,61% P6.1.1.b_Y1 796 880,43 5,99% 2 241 553,63 3,05% P6.1.1.c_Y1 1 029 328,40 7,74% 2 556 713,15 3,48% P6.1.1.d_Y1 499 815,41 3,76% 1 412 667,32 1,93% P6.2.1.a_Y1 387 856,40 2,92% 1 055 440,69 1,44% P6.2.1.b_Y1 967 434,79 7,27% 3 700 511,37 5,04% P6.2.2.a_Y1 761 344,78 5,72% 2 751 203,72 3,75% P6.2.3.a_Y1 1 959 955,06 14,73% 7 106 697,78 9,68% P6.2.4.a_Y1 360 540,82 2,71% 2 036 006,00 2,77% P6.2.4.b_Y1 474 670,44 3,57% 2 859 059,17 3,90% P6.2.4.c_Y1 221 232,65 1,66% 861 107,64 1,17% P6.2.4.d_Y1 158 771,94 1,19% 613 187,40 0,84% P6.3.1.a_Y1 250 615,00 1,88% 860 122,63 1,17% P6.3.1.b_Y1 425 757,94 3,20% 1 724 756,87 2,35% P6.3.2.a_Y1 501 426,89 3,77% 1 797 348,71 2,45% P6.4.1.a_Y1 490 128,52 3,68% 1 238 928,15 1,69% P6.4.1.b_Y1 220 330,52 1,66% 696 267,90 0,95% P6.4.1.c_Y3 262 488,13 1,97% 949 625,00 1,29% P6.4.2.a_Y1 84 515,94 0,64% 225 291,58 0,31% P6.4.2.b_Y1 152 781,38 1,15% 445 885,56 0,61% P6.4.2.c_Y1 138 673,94 1,04% 385 203,69 0,52% P6.4.3.a_Y1 272 554,38 2,05% 702 020,63 0,96% P6.4.3.b_Y3 228 256,38 1,72% 1 029 618,63 1,40% P6.4.4.a_Y1 232 233,36 1,75% 781 891,58 1,07% P6.4.4.b_Y1 224 698,38 1,69% 614 834,24 0,84% P6.4.4.c_Y1 282 811,56 2,13% 657 419,06 0,90% P6.4.4.d_Y1 160 040,45 1,20% 603 079,96 0,82% P6.4.4.e_Y1 530 460,70 3,99% 1 275 335,23 1,74% Transversal activities 832 518,80 6,26% 7 100 042,31 9,68% Task 6.1 202 514,38 1,52% 1 900 406,69 2,59% Task 6.2 143 843,22 1,08% 1 597 543,72 2,18% Task 6.3 106 406,84 0,80% 768 367,55 1,05% Task 6.4 379 754,37 2,85% 2 833 724,35 3,86% TOTAL WP6 13 303 415,09 100,00% 49 466 149,25 73 379 540,00 67,41% DELIVERABLE D1.8 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 146 Work Package 7 Task/Project ID Budget allocated for Y3 % Budget allocated for Y3 / total WP budget allocated for Y3 Total Budget allocated Total WP budget at proposal stage % Project Total Budget allocated / Total WP budget at proposal Projects 1 762 852,99 65,98% 4 870 385,41 22,25% P7.2.2.a_Y1 763 353,12 28,57% 2 034 313,74 9,29% P7.2.2.b_Y1 764 481,93 28,61% 1 887 277,75 8,62% P7.3.3.a_Y1 235 017,94 8,80% 948 793,91 4,33% Transversal activities 908 781,92 34,02% 7 562 888,71 34,55% Task 7.1 159 184,83 5,96% 1 291 268,67 5,90% Task 7.2 398 239,20 14,91% 3 254 621,85 14,87% Task 7.3 351 357,90 13,15% 3 016 998,19 13,78% TOTAL WP7 2 671 634,91 100,00% 12 433 274,12 21 889 938,00 56,80% PARC – ANNEX I AWPY3 – page 147 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio Annex I AWP Y3 PARC PROJECT PORTFOLIO PARC – ANNEX I AWPY3 – page 148 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio Table of Contents Annex AWPY3 - Parc Project portfolio Annex I AWP Y3 .............................................................................................................................. 147 WP4 Monitoring and exposure – 21 PROJECTS ............................................................................ 151 T4.1 Human Biomonitoring – 9 PROJECTS ............................................................................................ 151 A4.1.1 Design, alignment and fieldwork of HBM studies – 5 PROJECTS ................................................................... 152 S4.1.1.1 Development of supporting materials for harmonized EU HBM conduct ..................................................... 152 S4.1.1.2 General population survey – 1 PROJECT ........................................................................................................ 152 P4.1.1.2.a_Y1_GenHBMSurvey_VITO .......................................................................................................................... 152 S4.1.1.3 Targeted surveys ............................................................................................................................................ 156 S4.1.1.4 Occupational surveys – 4 PROJECTS .............................................................................................................. 156 P4.1.1.4.a_Y1_OccupFeasability_TTL ........................................................................................................................... 156 P4.1.1.4.b_Y1_SentinelSystem_KULeuven .................................................................................................................. 158 P4.1.1.4.c_Y1_HealthCareSurvey_TTL_SRU ................................................................................................................. 161 P4.1.1.4.d_Y1_OccupWaste_ENSP_TTL ....................................................................................................................... 164 S4.1.1.5 Implementation of innovative methods ........................................................................................................ 166 A4.1.2 Laboratory analysis and quality assurance .................................................................................................... 166 A4.1.3 Link exposure and health related information – 2 PROJECTS ........................................................................ 167 S4.1.3.1 Propose health-based HBM guidance values – 1 PROJECT............................................................................ 167 P4.1.3.1.a_Y1_DerivationofHBM-GVs_UBA ................................................................................................................. 167 S4.1.3.2 Identify effect biomarkers for prioritized chemicals, populations and health outcomes ............................. 169 S4.1.3.3 Link HBM studies to health examination and dietary studies – 1 PROJECT .................................................. 169 P4.1.3.3.a_Y1_RoadmapLinkingHBMhealth_SpF_VITO ............................................................................................... 169 A4.1.4 Data Management and analysis – 1 PROJECT ................................................................................................ 171 S4.1.4.1 Data management ......................................................................................................................................... 171 S4.1.4.2 Data analysis – 1 PROJECT ............................................................................................................................. 172 P4.1.4.2.a_Y1_DataAnalysisHBM4EU_VITO................................................................................................................. 172 A4.1.5 Preparation of a sustainable monitoring and surveillance system for Europe – 1 PROJECT ......................... 174 P4.1.5.a_Y1_SustainHBMSystem_VITO ....................................................................................................................... 174 T4.2 Environmental and Multisource Monitoring – 3 PROJECTS ............................................................ 176 P4.2.a_Y1_ENVMonitoringPilotSurvey_INERIS_AU ..................................................................................................... 178 P4.2.b_Y2_ENVMonitoringframe_AU_INERIS ............................................................................................................. 180 P4.2.c_Y3_Human exposure_INERIS_AU ..................................................................................................................... 183 T4.3 Innovative methods and tools for monitoring and surveys – 9 PROJECTS ....................................... 189 A4.3.1 Transversal actions –3 PROJECTS ................................................................................................................... 190 P4.3.1.b_Y1_T02-QAQC_WR ........................................................................................................................................ 190 P4.3.1.c_Y1_T03_EWStools_SLU ................................................................................................................................. 192 P4.3.1.d_Y1_T04-Data Processing Workflow_EHESP................................................................................................... 194 A4.3.2 Human samples based proof-of-concepts – 3 PROJECTS .............................................................................. 196 P4.3.2.a_Y1_H01-Perinatal exposure_INRAE ............................................................................................................... 196 P4.3.2.b_Y2_H02-Occupational exposure_INRS .......................................................................................................... 198 P4.3.2.c_Y3_H03-Complementary developments_JSI-UAntwerpen ........................................................................... 201 A4.3.3 Environment samples based proof-of-concepts – 2 PROJECTS ..................................................................... 205 P4.3.3.a_Y1_EO1-Wastewater based epidemiology_UFZ-UBATH ............................................................................... 205 P4.3.3.b_Y2_EO2-Sentinel animals_ONIRIS ................................................................................................................. 207 A4.3.4 Food samples based proof-of-concepts – 1 PROJECT .................................................................................... 209 P4.3.4.a_Y2_F02Food items exposure _ANSES ......................................................................................................... 209 WP5 Hazard Assessment - 13 PROJECTS ...................................................................................... 212 T5.1 Toxicity testing addressing data gaps of concern 5 PROJECTS ........................................................ 212 A5.1.1 Closing data gaps of concern for human health – 3 PROJECTS ..................................................................... 212 P5.1.1.a_Y1_Toxins_BfR_UNIVIE ................................................................................................................................. 212 P5.1.1.b_Y1_BPA_HumTox_BfR ................................................................................................................................... 215 P5.1.1.c_Y3_TG+ EnnB1_ANSES ................................................................................................................................... 218 A5.1.2 Toxicity assessment addressing data gaps of concern (Environment) – 2 PROJECTS .................................... 220 PARC – ANNEX I AWPY3 – page 149 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio P5.1.2.a_Y1_NaturalToxinsAqua_UGent ..................................................................................................................... 220 P5.1.2.b_Y1_BPAalternatives_BPI_MU ........................................................................................................................ 222 T5.2 Innovative methods and tools for toxicity testing and modelling - 5 PROJECTS .............................. 224 A5.2.1 Innovative methods and tools for toxicity testing and modelling – 5 PROJECTS .......................................... 224 P5.2.1.a_Y1_NGTXCs_INRAE ........................................................................................................................................ 224 P5.2.1.b_Y1_MD-EDC_BfR ........................................................................................................................................... 227 P5.2.1.c_Y1_EDThDisruption_DTU............................................................................................................................... 229 P5.2.1.d_Y1_Immunotox_Inserm ................................................................................................................................ 232 P5.2.1.e_Y1_DNT-ANT_ UFZ_IUF_NIPH ....................................................................................................................... 235 A5.2.2 Innovative methods and tools for toxicity testing and modelling for Environmental Toxicology / Ecotoxicology .................................................................................................................................................................... 237 T5.3 Quantitative systems toxicology and development of new AOPs - 3 PROJECTS .............................. 237 A5.3.1 Prioritized NAM-based mechanistic hazard characterization – 1 PROJECT ................................................... 238 P5.3.1.a_Y1_SystemsToxicology_UL-LACDR ................................................................................................................ 238 A5.3.2 AOP development based on integration – 1 PROJECT ................................................................................... 240 P5.3.2.a_Y1_AOPDevelopment_Inserm ...................................................................................................................... 240 A5.3.3 Translation to human pathophysiology ......................................................................................................... 243 A5.3.4 PBTK models and quantitative systems toxicology – 1 PROJECT ................................................................... 243 P5.3.4.a_Y1_PBK_Kinetics_Fraunhofer ........................................................................................................................ 243 WP6 Innovation in regulatory risk assessment – 28 PROJECTS .................................................. 246 T6.1 Integrated Approaches to Testing and Assessment of Chemicals 4 PROJECTS ................................. 246 A6.1.1 Development of IATAs for regulatory purposes – 4 PROJECTS ...................................................................... 247 P6.1.1.a_Y1_HumanRelevance_RIVM ......................................................................................................................... 247 P6.1.1.b_Y1_IATA-ED_ UAntwerpen ............................................................................................................................ 249 P6.1.1.c_Y1_IATA_GENTOX_ Sciensano ....................................................................................................................... 251 P6.1.1.d_Y1_IATA_STOT_UL-LACDR ............................................................................................................................ 254 A6.1.2 Evaluation of IATAs through case studies ...................................................................................................... 256 A6.1.3 Stakeholder engagement ............................................................................................................................... 256 T6.2 Integrative exposure and risk assessment - 8 PROJECTS ................................................................ 256 A6.2.1 Aggregate exposure from multiple sources and routes for general population and workers – 2 PROJECTS 257 P6.2.1.a_Y1_SourcetoDose_VITO ................................................................................................................................ 257 P6.2.1.b_Y1_Aggregate_Anses .................................................................................................................................... 259 A6.2.2 Modelling exposure through life – 1 PROJECT ............................................................................................... 261 P6.2.2.a_Y1_PBPK_INERIS_AUTH ................................................................................................................................ 261 A6.2.3 Mixture exposure and risk assessment – 1 PROJECT ..................................................................................... 263 P6.2.3.a_Y1_RealLifeMixtures_RIVM ........................................................................................................................... 263 A6.2.4 Human health impact assessment and risk indicators – 4 PROJECTS ............................................................ 265 P6.2.4.a_Y1_HIADataAvailability_VITO ........................................................................................................................ 265 P6.2.4.b_Y1_HIAMethod_UU-IRAS .............................................................................................................................. 267 P6.2.4.c_Y1_HIACaseStudies_UU-IRAS ........................................................................................................................ 269 P6.2.4.d_Y1_HIAIndicators_VITO ................................................................................................................................. 271 T6.3 Review of risk assessment methodologies - 3 PROJECTS ............................................................... 273 A6.3.1 Substance and effect specific reviewers – 2 PROJECTS ................................................................................. 274 P6.3.1.a_Y1_SubstanceRA_SU ..................................................................................................................................... 274 P6.3.1.b_Y1_EffectRA_BPI ........................................................................................................................................... 276 A6.3.2 Use of tools, criteria, and methods – 1 PROJECT ........................................................................................... 279 P6.3.2.a_Y1_ToolsRA_SU ............................................................................................................................................. 279 T6.4 Transposing results to regulatory risk assessment methodologies 13 PROJECTS............................. 282 A6.4.1 Develop regulatory relevant approaches and methods for chemical mixtures – 3 PROJECTS ...................... 283 P6.4.1.a_Y1_OPREMIXCS1_BRUNEL_UGot .................................................................................................................. 283 P6.4.1.b_Y1_MONAMMIXCS2_UFZ ............................................................................................................................. 285 P6.4.1.c_Y3_Skinsenmix_RegionH ............................................................................................................................... 287 A6.4.2 Facilitate the regulatory acceptance and use of new methods – 3 PROJECTS .............................................. 289 PARC – ANNEX I AWPY3 – page 150 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio P6.4.2.a_Y1_LandscapingSurv_UNIBAS ....................................................................................................................... 289 P6.4.2.b_Y1_NGRApractive_VKM_NIPH ...................................................................................................................... 292 P6.4.2.c_Y1_NAMAM_UT ............................................................................................................................................ 294 A6.4.3 Developing information transfer structures and enforcement methodology for chemicals in articles to support the transition to a circular economy – 2 PROJECTS .......................................................................................................... 296 P6.4.3.a_Y1_SuProM_MU ............................................................................................................................................ 297 P6.4.3.b_Y3_ENFORCE_KemI ....................................................................................................................................... 299 A6.4.4 Risk assessment to support and promote efficient overall protection of biodiversity – 5 PROJECTS ........... 301 P6.4.4.a_Y1_CRNCS1_KEMI ......................................................................................................................................... 301 P6.4.4.b_Y1_PPPEXPCS2_UFZ ...................................................................................................................................... 303 P6.4.4.c_Y1_PPPEFFCS3_UFZ ....................................................................................................................................... 305 P6.4.4.d_Y1_PPPBENCHCS4_UKOLD ............................................................................................................................ 307 P6.4.4.e_Y1_PPPOSCS5_ISCIII ...................................................................................................................................... 309 WP7 FAIR data – 3 PROJECTS ................................................................................................... 313 T7.2 Data libraries – 2 PROJECTS .......................................................................................................... 313 A7.2.1 Mapping the PARC Data Landscape ............................................................................................................... 314 A7.2.2 PARC FAIR data hub – 2 PROJECTS ................................................................................................................ 314 P7.2.2.a_Y1_chemicals-in-environment_MU_VITO ..................................................................................................... 314 P7.2.2.b_Y1_HBMdatasets_VITO ................................................................................................................................. 317 A7.2.3 Solutions for FAIR data: development and implementation ......................................................................... 320 A7.2.4 Standards and harmonisation........................................................................................................................ 320 T7.3 Innovative analyses – 1 PROJECT .................................................................................................. 320 A7.3.1 Innovative methods for combined analyses of FAIR (heterogeneous) data ................................................. 320 A7.3.2 Methods for uncertainty characterisation, propagation and quantification as a basis for harmonisation in RA 320 A7.3.3 Novel computational methods for integrating and extracting knowledge from non-structured data – 1 PROJECT 320 P7.3.3.a_Y1_ALT-IST_IISPV .......................................................................................................................................... 320 A7.3.4 Identify additional needs in PARC for innovative analyses and promising evolutions in the data science landscape, and translate them in use cases for evaluation ............................................................................................. 323 List of Project Reports, Project Key Landmarks and Deliverables, Additional deliverables, Milestones to which the projects contribute.......................................................................................................... 324 PARC – ANNEX I AWPY3 – page 151 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio WP4 Monitoring and exposure – 21 PROJECTS Guided by regulatory needs, WP4 aims to develop and improve the chemical monitoring and exposure assessment capacities in Europe as depicted in figure 1. The overall goal is a better understanding of the environmental and human exposure to chemicals from multiple sources including pathways of exposure between the environment and humans. In support of a “one substance, one assessment approach” new monitoring approaches will be applied to complement existing monitoring schemes. Robust, reliable and fit-for-purpose innovative tools and methods will be developed, primarily to support and facilitate exposure assessment for vulnerable sub-populations and the early warning detection of chemicals of emerging concern. The work under WP4 is divided into three tasks that address the objectives of developing a) the human biomonitoring platform initiated in HBM4EU, b) environmental and multisource monitoring, and c) innovative methods and tools for monitoring. Fig 1: WP4 General approach and vision T4.1 Human Biomonitoring – 9 PROJECTS A HBM survey targeting the general population will constitute the basis of a well aligned human biomonitoring (HBM) surveillance programme for chemical exposure of European citizens and will generate internal exposure data (see Fig.2). Statistically derived internal exposure reference values will allow for the evaluation of spatial and temporal trends in chemical exposure and monitoring of the impact of regulations and the EU’s Chemicals Strategy for Sustainability. In addition, targeted HBM surveys will address specific research and policy questions related to vulnerable groups (young children, pregnant women), highly exposed groups (workers, hotspot residents) or time trends. Priorities will be identified in cooperation with WP2 (‘A common science-policy agenda’). Further to the work achieved in HBM4EU (https://www.hbm4eu.eu) and in coordination with WP9 (‘Building infrastructural and human capacities’), activities are being designed and implemented to ensure the quality and comparability of the HBM results. Harmonisation and improvement of analytical methods across laboratories will be implemented, defining reference analytical methods when possible. Special efforts will also be devoted into developing useful tools for the improvement of the HBM laboratory network. Task 4.1 will further develop the HBM4EU strategy to derive Health-Based Guidance Values (HBM-GVs) for the general and/or the occupational population. Effect biomarkers will complement exposure biomarkers to evaluate associations between chemical exposure and adverse health effects. Issues related to the linkage of HBM, health examination, occupational and dietary surveys will be identified and solved with support of WP7 (‘FAIR Data’). In collaboration with WP2 co-leaders and partners, the ultimate goal of this task is to prepare a long-term sustainable HBM and surveillance system for exposure to chemicals in Europe. PARC – ANNEX I AWPY3 – page 152 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio Fig 2: PARC Aligned Studies A4.1.1 Design, alignment and fieldwork of HBM studies – 5 PROJECTS S4.1.1.1 Development of supporting materials for harmonized EU HBM conduct No project submitted at present. S4.1.1.2 General population survey – 1 PROJECT P4.1.1.2.a_Y1_GenHBMSurvey_VITO Project Title General population human biomonitoring survey Project Acronym (15 letters max) GenHBMSurvey Project Manager Liese Gilles liese.g[email protected] VITO Belgium Deputy Project manager Susana Pedraza Diaz ISCIII PARC <[email protected]> ISCIII Spain Expected starting date PARC (Month number) 1 Expected duration 81 PARC Workpackage number 4 PARC Task/Activity/Subactivity: 4.1.1.2 Project Id P4.1.1.2.a_Y1_GenHBMSurvey_VITO Status: Implementation Summary of the project This project is of relevance for all regulatory frameworks governing chemical production, use, environmental release, and exposure in various contexts, including those aimed at safeguarding environmental and human health. Demonstrating the effectiveness of existing policies is vital for public trust and increasing transparency towards industry and stakeholders. In this project biomarkers of chemical pollutants will be assessed in human biological samples (urine, PARC – ANNEX I AWPY3 – page 255 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio repeated dose toxicity), as these requirements go beyond studying liver effects. Nevertheless, such an IATA will partially inform the information requirements needed for STOT Single Exposure (SE) and STOT Repeated Exposure (RE) classification as defined under REACH. These include respectively 8.5.1 (acute toxicity - annex VII), 8.5.2 or 8.5.3 (acute toxicity - annex VIII), and 8.6.1 (short-term repeated dose toxicity study, 28 days - annex VIII), 8.6.2. sub-chronic toxicity study (90-day) (annex IX). Note that in this project we intend to produce a quantitative assessment of the involved assays in relation to the adverse outcome, which is an important aspect for STOT SE and STOT RE classification. Key words Integrated Approaches for Testing and Assessment (IATA), systemic toxicity, liver, fibrosis, (quantitative) Adverse Outcome Pathway (AOP), key events Link to the PARC Description of Action (DoA) This project responds to Specific objective 3 (SO3) “European risk assessors, their scientific network and the wider stakeholder community have access to the R&I capacities required to implement innovative chemical RA”, and more specifically to Operational Objective 9 “Develop tools to facilitate the acceptance and use of PARC results in regulatory RA processes and support (existing) standardisation and validation processes for innovative approaches to RA”. Links within PARC (WPs/Tasks/Activities/Projects) The project is linked within the following PARC activities: For T6.1 the project is linked to three other projects in T6.1: 1. P6.1.1.a_Y1_HumanRelevance_RIVM 2. P6.1.1.b_Y1_IATA_ED_UAntwerpen 3. P6.1.1.c_Y1_IATA_GENTOX_Sciensano To maximize synergy across the T6.1 projects, core teams addressing common elements will be established. These core teams include “AOP networks”, “Quantitative AOPs”, and “IATA development/evaluation”. The project team involved in the project on human relevance will closely collaborate with the other three projects, in particular with the core teams on AOP networks and quantitative AOPs. The work described in this project is connected to other WPs in PARC, in multiple ways. Firstly, the proposed priorities regarding regulatory frameworks to be addressed will be confirmed with stakeholders in close collaboration with WP2 “A common science-policy agenda” and WP3 “Synergies, collaboration and awareness”. Secondly, we will closely collaborate with WP5 “Hazard assessment” on various topics related to IATA development. These topics include: a) mapping of existing AOPs and associated NAMs for endocrine disruption; b) development of (quantitative) AOP networks using, among others, data generated in WP5; c) linkage to QIVIVE and PBK modeling (T5.3); and c) evaluation of IATA through case studies. For the latter, we will also closely collaborate with T6.2 – T6.4. The case studies also provide a link to WP7 “FAIR data’, in which analysis of the uncertainties associated with the IATA will be one of the use cases. Lastly, this work relates to WP9 “Capacities”, since valuable learnings will be taken up in relevant training courses. Links outside PARC Furthermore, the project is closely linked to the Horizon2020 projects EU-ToxRisk, RISK-HUNT3R, ONTOX and PrecisionTox, and to work ongoing at OECD in relation to AOP development (OECD AOP programme) and IATA case studies. As such, regular interactions with the OECD Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST) and the OECD Working Party for Hazard Assessment (WPHA) are foreseen. Key PARC Deliverables and Milestones to which the project contributes The output from this project will substantially contribute to the following key deliverables of WP6: ● D6.5; D6.12: Reports on IATAs and associated case studies (M42; M81; Sciensano) ● D6.11: Harmonized workflow for human relevance assessment of AOPs and associated NAMs (M72, RIVM) PARC – ANNEX I AWPY3 – page 256 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio ● AD5.5 Inventory of the available (networks of) AOPs, prioritisation and establishment of the framework for further development in PARC (M12; INSERM) ● AD6.9: Report on draft IATAs and associated case studies (new delivery date M30; UL-LACDR) Partners List UL-LACDR (NL), WU-TOX (L), INSERM (FR), Ugent (BE), AUTH (GR), MU (CZ), IISPV (ES), STAMI (NO), ISS (IT), IRFM (IT), WFSR (NL). Schedule Starting date: 01/05/2022 (M1) Expected ending date: 30/04/2025 (M36) Cost: Expected PM for the third year of the project: 48 PM Expected ODC for the third year of the project: 94 084 € A6.1.2 Evaluation of IATAs through case studies This activity is incorporated in the projects listed under A6.1.1. A6.1.3 Stakeholder engagement This activity is incorporated in the projects listed under A6.1.1. T6.2 Integrative exposure and risk assessment - 8 PROJECTS The aim of this task is to develop innovative and practical approaches for human health risk and impact assessment of single, aggregated and combined exposure to chemicals via multiple sources across regulatory silos and routes during lifetime. Relative contributions of sources and routes will be determined. Living and working environment as well as chemical transfer from soil to water, food, and air and migration from consumer products, articles and materials will be integrated. For estimating and reconstructing chemical exposure through life, accounting for varying exposure scenarios and physiological and biochemical characteristics over time, PBK models will be developed. Simulations of concentrations in target tissues will be linked to AOPs and IATAs. Finally, data availability and methodologies to perform health impact and cost-benefit assessment for prioritised chemicals, exposure routes, windows of exposure, subpopulations, geographical locations, and health outcomes will be improved. Fig 10: W6.2: Risk and health Impact Assessment PARC – ANNEX I AWPY3 – page 257 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio A6.2.1 Aggregate exposure from multiple sources and routes for general population and workers – 2 PROJECTS P6.2.1.a_Y1_SourcetoDose_VITO Project Title Developing, performing and validation of source to dose modelling including selected case studies Project Acronym (15 letters max) SourcetoDose Project Manager Katleen De Brouwere [email protected] VITO BE Deputy Project manager Radu Duca [email protected] LNS LU Expected starting date PARC (Month number) 1 Expected duration 36 PARC Workpackage number 6 PARC Task/Activity/Subactivity: 6.2.1 Project Id P6.2.1.a_Y1_SourcetoDose_VITO Status: Implementation Summary of the project This project aims to model from sources to doses, the human exposure of general population to chemicals, potentially arising from a variety of sources and routes. Sources include different types: environmental sources including 1) emissions from industrial facilities, traffic and households, etc. 2) diffuse environmental sources (e.g., historical soil contamination, water etc), and 3) consumer sources present in our everyday life, (e.g., construction products, household products, etc.) potentially releasing chemicals that may enter our bodies. It is anticipated that for some source and route of exposure, models do exist, but are (overly) conservative in nature because of their intended uses for screening purposes. However, when it comes to combination of exposures from different sources into an aggregated exposure (and comparison with HBM values) and health impact assessment, realistic external exposure models are crucial, and needed for policy makers (e.g., in view of comparing impact of different policy or risk management options). This project is connected to the project on aggregate exposure modelling. The scope of this project will be routes and sources for which realistic exposure models are currently lacking. Where models are lacking, they will be developed. Where possible, we will rely on existing models and improve them in order to shift from screening models to higher tier models generating realistic exposure estimates. This project focus is on modelling as a complementary tool to human biomonitoring, for the general population (occupational exposure is out of scope). Case studies will be tailored toward chemical classes in line with PARC projects (e.g., case studies on PFAS, flame retardants, metals, pesticides). The ultimate goal is to come up with robust, mechanistic model(s) and tools which are, at the same time relatively simple in use for risk assessors. Main expected outputs of the project  Improvement of existing models for generating realistic exposure assessment for selected consumer articles or products, and environmental sources  Development of new model(s) for routes and sources for which there is currently a lack of models (for selected sources)  Transcription of the conceptual model(s) to T8.3 Outcomes and impacts expected for end-users and stakeholders The role of modelling in aggregate exposure assessment is that modelling offers a complementary tool to human biomonitoring to perform chemical risk assessment. PARC – ANNEX I AWPY3 – page 258 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio This project will make it possible to end-users to perform risk assessment for chemicals (environment and consumer exposure) covered in this project. It will offer end-users the opportunity 1) to expand the assessment to other groups not included in HBM studies ((e.g. specific age groups, vulnerable groups), 2) to assess the relative contribution of different sources and exposure routes (given that that the models will generate realistic exposure estimates for each source and route), and 3) to calculate the impact of risk management options (e.g. predicting impact of restrictions, mitigations). The latter can inform policy makers about the most efficient risk management strategies thus allowing for better informed decision making. Key words: human exposure, modelling, consumer exposure, exposure via the environment, realistic exposure modelling, migration, articles Link to the PARC Description of Action (DoA) OO5: The project will identify data required for source to dose modelling for priority chemicals and exposure scenarios across Europe. The project will use data and knowledge generated and published by other past and ongoing R&I projects and initiatives. OO7: Based on data gaps that appear from the data and models inventories, studies to fill these gaps may be initiated. OO8: The project will support the provision of environmental and multisource data for regulatory purposes, since environmental and multisource data are key elements for parameterization and/or verification of source to dose models. OO10: As the project will use data that are generated outside PARC and by other PARC projects, and will generate data that can be used by other activities in and outside of PARC, implementation of FAIR data practices is a prerequisite. OO13: The project will be developing and carrying out training and exchange programmes regarding source to dose models. Links within PARC (WPs/Tasks/Activities/Projects)  Connection with T4.1 (HBM data from T.4.1 will be used to validate the model outcome)  Connection with A6.2.1 Interoperability of models for aggregate exposures:  gaps identified will steer the priorities in 6.2.1  model outcomes generated in this project can be included in aggregate exposure modelling in 6.2.1.  Connection with T8.3: outcome (model) will be taken up in T8.3  Project “Strategy for aggregate exposure from general life and occupational exposures” (project P6.2.1.b_Y1_Aggregate_ANSES)  Projects from T8.3 Links outside PARC This project will start from the work of previous initiatives such as the ones from ISES Europe and the REACH Exposure Expert Group (REEG), HBM4EU (WP 12), and 7th FP projects (e.g., 4-FUN) Key PARC Deliverables and Milestones to which the project contributes  AD6.3. Roadmap on aggregated exposure strategy through different living environments sources and routes (M12)  D6.1. 1st Report on aggregate exposure for general population and workers, and source to dose models applied to case studies (M36) Partners List: VITO (BE); RIVM (NL); ANSES (FR); LNS (LU); IVV (DE); CSTB (FR); KWR (NL); IVL (SW); NIJZ (SI); FOPH (CH); GeoZS (SI); FMUL (PT), UoB (UK), IISPV (ES) Schedule Starting date: 01/05/2022 (M1) Expected ending date: 30/04/025 (M36) PARC – ANNEX I AWPY3 – page 259 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio Cost: Expected PM for the third year of the project: 33 PM Expected ODC for the third year of the project: 20 525 € P6.2.1.b_Y1_Aggregate_Anses Project Title Strategy for aggregate exposure from general life and occupational exposures Project Acronym (15 letters max) Aggregate Project Manager Crépet Amélie [email protected] ANSES France Deputy Project manager David Vernez [email protected] UNISANTE Switzerland Expected starting date PARC (Month number) 1 Expected duration 48 PARC Workpackage number 6 PARC Task/Activity/Subactivity: 6.2.1 Project Id P6.2.1.b_Y1_Aggregate_ANSES Status: Implementation Summary of the project In the context of a compartmentalized view of risk assessment, this project aims to advance knowledge on the combination of various exposure environments including occupational and general life exposures. It will help to propose a more integrative risk assessment and management crossing regulatory silos. This project will draw up the strategy to aggregate exposures from multiple sources and routes in considering both general life and occupational exposures. It is divided into three parts. The first one aims to review available models, tools and data and draw a functional design for model connection. The second part is to work on methods and criteria to perform aggregate exposure and the last part is to organize and start the relevant case studies selected from the defined criteria and PARC priorities. Building from current knowledge, this project is an important step to propose advanced aggregate exposures assessment from multiple sources and routes. It will provide a better understanding of the main sources and routes of exposure during occupational and general life to support effective risk management measures. Main expected outputs of the project The outputs for model interoperability and data inventory part are: selection of models for further analysis, models and tools description with their structural analysis, functional design for model connection for T8.3, data inventory for T7.1 and data gaps to be feed by T4.1 and T4.2. The outputs for methods for aggregate exposure part are: strategy and roadmap for aggregate risk assessment, innovative methods to perform aggregate risk assessment, criteria for prioritisation of case studies and advance knowledge on the combination of various exposure environments including occupational and general life exposures. The outputs for case studies for aggregate exposure part are: selection of relevant case studies of aggregate exposure including general life and occupational exposures, aggregated exposure results and prioritization of main sources and routes of exposure from general life and occupational environments. Outcomes and impacts expected for end-users and stakeholders Provide tools to facilitate comparisons between entry routes and exposure situations and, ultimately, prioritize areas for action and prevention. This project will also make it possible to end-users to perform risk assessment from several sources and routes of exposure. It will make possible to account for both general life and work activities in risk assessment. Concrete case studies will be conducted for prioritized chemicals. PARC – ANNEX I AWPY3 – page 260 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio Key words: Aggregate exposure, multiple sources, multiple routes, risk mitigations, occupational exposures, general life exposures, consumer exposure, environmental exposure. Link to the PARC Description of Action (DoA) This project responds to the PARC operational objectives OO4: Actively foster regulatory uptake of PARC knowledge, OO6: Communicate & disseminate PARC knowledge to increase citizen’s understanding/awareness of chemical RA, OO12: Develop models and innovative concepts for RA and deliver toolboxes to promote their acceptability and uptake, OO9: Develop tools to facilitate the acceptance and use of PARC’s results in regulatory RA processes and support (existing) standardisation and validation processes for innovative approaches to RA and OO13: Build capacities by developing and carrying out training and exchange programmes in chemical RA. This project will develop methods, toolboxes, and organize relevant data to combine exposure from various environments including occupational and general life exposures. In identifying main sources and routes of exposure during occupational and general life, the output of the project will help to prioritize risk management measures. Training to the new methods and tools will be proposed with T8.3 to the different stakeholders. Links within PARC (WPs/Tasks/Activities/Projects) This project is also strongly connected to other projects from T6.2. As example aggregate exposures can be used as input in mixture (P6.2.3) and health impact projects (P6.2.4). The output of the sources to dose (P6.2.1.a) and PBPK projects (P6.2.2.a) can be used as input of this project. This project will be strongly connected to the T8.3 on integrative models in involving the task leader WRBIOM. The objective is to deliver the functional design to task T8.3 for its implementation. The data inventory will be conducted in connection with the T4.1 and T4.2 and the results of the data gap analysis will be discussed with the leaders to see how they can be handled. A connection with T7.3 on methods to combine data to account for uncertainty will be also done as aggregate exposure can be a good case study. It can also propose input for training in WP9. Links outside PARC This project will start from the work of previous initiatives such as the ones from ISES Europe and the REACH Exposure Expert Group (REEG). It is also linked to the Scientific Committee Consumer Safety. Key PARC Deliverables and Milestones to which the project contributes AD6.3. Roadmap on aggregated exposure strategy through different living environments sources and routes (including inventory of databases, models and tools (M12) D6.1. 1st Report on aggregate exposure for general population and workers, and source to dose models applied to case studies (M36) AD6.21. Report describing the results of the aggregate strategy and its application (M48) Partners List: ANSES (FR), UNISANTE (CH), RIVM (NL), VITO (BE), UU (SE), NIOM (PL), INSA (PT), TNO (NL), NIJZ (SI), AU (DK), TTL (FI), SRU (NL), GeoZS (SI), LNS (LU), ISSeP (BE), CSTB (FR), EFSA (EU), MU (CZ), WR-BIOM (NL), CSIC (ES), INRS (FR), NIPH (NO), KWR (NL), IVL (SE), ISCII (ES), FOPH (CH), STAMI (NO), FMUL (PT), ENSP-UNL (PT), UOB (UK), BPI (EL), AUTH (EL). Schedule Starting date: 01/05/2022 (M1) Expected ending date: 30/04/2026 (M48) Cost: Expected PM for the third year of the project: 109 PM Expected ODC for the third year of the project: 94 125 € PARC – ANNEX I AWPY3 – page 261 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio A6.2.2 Modelling exposure through life – 1 PROJECT P6.2.2.a_Y1_PBPK_INERIS_AUTH Project Title Refinement and development of PBPK models for human risk assessment Project Acronym (15 letters max) PBPK Project Manager Aude RATIER aude.ra[email protected] INERIS France Deputy Project manager Spyros KARAKITSIOS spyros.karakitsios@gmai l.com AUTH Greece Expected starting date PARC (Month number) 1 Expected duration 48 PARC Workpackage number 6 PARC Task/Activity/Subactivity: 6.2.2 Project Id P6.2.2.a_Y1_PBPK_INERIS_AUTH Status: Implementation Summary of the project Physiologically Based Pharmacokinetic (PBPK) models are essential tools in toxicokinetic modelling and risk assessment as they describe the Absorption, Distribution, Metabolism, and Excretion (ADME) processes in the human body. PBPK models are able to focus on the effective dose at the target site, providing a better characterization of the relationship between exposure dose and adverse effects (Andersen, 1995; Verner et al., 2010). Given the growing interest in using PBPK models in the risk assessment process, guidelines for appropriate extrapolations of species, doses, and exposure scenarios have been proposed. The mechanistic basis of PBPK models is well adapted to toxicological risk assessment (US EPA, 2006; IPCS, 2010; OECD, 2021), in particular for dealing with extrapolations inherent to these domains (in vitro to in vivo, laboratory animals to humans, various exposure or dosing schemes, etc.). The HBM4EU project reviewed available PBPK models for several compounds, highlighting a lack of toxicokinetic data for many prioritized compounds and a lack of models for sensitive populations such as pregnant women and their fetuses, newborns, young children, or the elderly. In this PARC project, PBPK models will be refined or developed to address population sub-group sensitivities, integrating multiple exposure routes and sources, and interpreting human biomonitoring data. Different sources of data will be used (either from literature or from synergies with WP5) for refining or developing PBPK models necessary for the use of internal dose metrics for risk assessment. Main expected outputs of the project PBPK models will be refined or developed to address population sub-group sensitivities, integrating multiple exposure routes (oral ingestion, inhalation, and dermal contact) and sources (occupational, consumer, and environmental), and new matrices of exposure predictive of specific exposure (e.g., hair or meconium for newborns). These models will be applied to biomonitoring data for one chemical or mixtures and will help to interpret them. The experimental needs with WP5 will be identified, and QSAR models will be used to obtain parameters related to kinetics and partitioning. The models developed in this task will be interoperable (in collaboration with WP7 and WP8) with open platform used for risk assessment. Outcomes and impacts expected for end-users and stakeholders As PBPK models are tools used to support risk assessors and managers, it is essential to provide models that are adapted to their requirements and that follow the most up-to-date guidance, e.g., the OECD document on the characterisation, validation and reporting of PBK models for regulatory purposes (Series on Testing and Assessment No. 331, ENV/CBC/MONO(2021)1). This project within PARC will focus on PARC – ANNEX I AWPY3 – page 262 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio the refinement or development of PBPK models for prioritized compounds and mixtures, e.g., with limited information, sensitive populations, and the aggregation of the various exposures. The models that will be proposed will be made interoperable (in collaboration with WP7 and WP8) with other modules in integrative open platforms used for risk assessment. Key words: PBK models; multi-route exposures; lifelong exposure; sensitive human sub-groups; metabolic interactions; barrier models. Link to the PARC Description of Action (DoA) The project responds to the PARC objectives OO5: the project will identify models for priority chemicals and sub-groups of population for which refine RA is needed across Europe. The project will use data and knowledge generated and published by other past and ongoing R&I projects and initiatives, OO7: Based on data gaps that appear from the PBK models inventory, studies to fill these gaps may be initiated, OO10: Implementation of FAIR data practices is a prerequisite. PBK models will be developed or implemented under the FAIR principles and OO12: PBK models will be developed to answer or to suggest innovative concepts for RA, and will be available on toolboxes to promote their acceptability. Links within PARC (WPs/Tasks/Activities/Projects) Activities undertaken in WP5 (Tasks 5.1, 5.2, 5.3) for the generation of toxicokinetic data and the development of AOP, WP8 (Task 8.3) for the model integration in an open platform, WP4 for the availability of HBM data. WP6: Other T6.2 projects that aim to link internal and external exposures from multiple sources (6.2.1) and for mixtures (6.2.3):  Strategy for aggregate exposure in order to confirm external exposure assessment with HBM data.  New risk assessment and exposome methodologies to reduce exposure and risk of real-life mixtures Links outside PARC Bisphenols, PFAS, pesticides, metals and mycotoxins have been priority compounds among the HBM4EU project and modelling efforts, as well as review of existing models and identification of gaps has been carried out. Some compounds are also endocrine disruptor compounds that are studied in the EURION cluster, specifically in the OBERON project. Links to the exposome projects, such as ATHLETE. The work in this area that is ongoing outside Europe is also considered (e.g., US EPA). Key PARC Deliverables and Milestones to which the project contributes AD6.4: Inventory of PBK models for assessing the internal exposure through life and for in-vitro-to-invivo extrapolation (M12) D6.2: 1st Report on innovative methods based on PBK models (M36) AD6.22: Case studies of the application of refined/developed PBPK models in the risk assessment process (M48) Partners List: INERIS (France), AUTH (Greece), IISPV (Spain), ANSES (France), RIVM (Netherlands), SLU (Sweden), NIPH (Norway), VITO (Belgium), WR-BIOM (Netherlands), WR-WFSR (Netherlands), IRFM (Italy), IVL (Sweden), TNO (Netherlands) Schedule Starting date: 01/05/2022 (M1) Expected ending date: 30/04/2026 (M48) Cost: Expected PM for the third year of the project: 93 PM Expected ODC for the third year of the project: 70 437 € PARC – ANNEX I AWPY3 – page 263 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio A6.2.3 Mixture exposure and risk assessment – 1 PROJECT P6.2.3.a_Y1_RealLifeMixtures_RIVM Project Title New risk assessment and exposome methodologies to reduce exposure and risk of real-life mixtures Project Acronym (15 letters max) RealLifeMixtures Project Manager Jacob Van Klaveren jacob.van.klavere[email protected] RIVM Netherlands Deputy Project manager Amélie Crépet Amelie.cre[email protected] Anses France Expected starting date PARC (Month number) 1 Expected duration 48 PARC Workpackage number 6 PARC Task/Activity/ Sub-activity: 6.2.3 Project Id P6.2.3.a_Y1_RealLifeMixtures _RIVM Status: Implementation Summary of the project The mixture concerns are reflected in the prioritisation process and were ranked as a high priority for many stakeholders and Member States. Furthermore, there is a need to regulate chemicals in such a manner that potential mixture effects are already considered in the registration or authorisation process (prospective risk assessment of mixtures). The project will build on scientific progress made on mixture risk assessment, by international organisations (such as EFSA, EEA and ECHA, EC-JRC, OECD), regarding hazard-based grouping of chemical and statistical approaches developed in previous project such as Euromix, HBM4EU and the EHEN exposome projects. The project combines risk assessment and epidemiological approaches to support scientific needs from Member States, DG SANTE and DG Environment. It will integrate the needs identified in the Chemical Strategy and the linked EC Policy Document SWD 250 final STAFF WORKING DOCUMENT Progress report on the assessment and management of combined exposures to multiple chemicals (chemical mixtures) and associated risks. The main objectives of the projects are to:  Build a common strategy to perform human risk assessment to chemical mixtures  Integrate exposome and risk assessment approaches  Prioritize real-life mixtures from HBM data  Develop hazard and kinetic information on prioritized mixtures  Study the link between mixture biomarkers of exposures and effects  Perform mixture risk assessment for prioritized mixtures Main expected outputs of the project  Prioritisation methods and/or grouping approaches to select the components to be considered;  Options to use (eco)toxicity and exposure data on the single components to predict mixture hazard and/or risks, through component-based approaches based on dose additivity;  Tiered approaches bringing together advances made for mixtures in regulatory risk assessment and in the field of exposome to refine the assessment depending on the availability and quality of exposure and hazard data Outcomes and impacts expected for end-users and stakeholders  EFSA, ECHA and EEA in future scientific opinions on risk assessment of mixtures PARC – ANNEX I AWPY3 – page 264 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio  EU Member States in communication towards stakeholders and the general public  Industry addressing the risk of mixtures when assessing the risk of new chemicals before entering the market The project includes training activities for end-users that will be organised by WP3 and WP9. Key words: Mixture, HBM, co-exposure, health effects, AOP, RPF, PBPK, risk assessment Link to the PARC Description of Action (DoA) This project responds to the PARC operational objectives OO4: Actively foster regulatory uptake of PARC knowledge, OO5: Promote cooperation with other R&I initiatives, OO6: Communicate & disseminate PARC knowledge to increase citizen’s understanding/awareness of chemical RA, OO12: Develop models and innovative concepts for RA and deliver toolboxes to promote their acceptability and uptake, OO9: Develop tools to facilitate the acceptance and use of PARC’s results in regulatory RA processes and support (existing) standardisation and validation processes for innovative approaches to RA and OO13: Build capacities by developing and carrying out training and exchange programmes in chemical RA. Real-life mixture project will fill-in basic science gaps to explore how human bio-monitoring can be used in practice for mixture risk assessment. The project is developing a strategy to perform mixture risk assessment (MRA) in three main steps: 1) Prioritisation of mixtures considering regulatory priorities 2) Collection and organisation of HBM and hazard data, and 3) Mixture risk assessment for prioritised mixtures and effects. The collected data and the developed approaches will be integrated in the MCRA toolbox which is a web-based computational environment addressing chemical mixtures and their hazard, exposure and risk assessment for health effects. Finally, the project will deliver methods, tools and practical results on prioritized chemical families and effects that will serve regulators to move forward on mixture questions Links within PARC (WPs/Tasks/Activities/Projects) This project has strong connection with:  WP1 : management and indicators  WP2: priority setting and uptake into policy  WP3: communication and dissemination of results  WP4: - Derivation of health-based HBM guidance values - Link human biomonitoring studies to health examination and dietary surveys  WP5: further hazard characterisation for mycotoxins, PFAS and heavy metals  WP7: link with external data sources (e.g., IPCHEM, Tox data or EFSA data)  WP8 : task 8.3 integrative models This project is strongly connected to other projects from T6.2. For, example aggregate exposures (T6.2.1) can be used as input in this project and development from PBPK projects (T6.2.2) will be directly applied in the context of mixture. This project is cooperating with T4.1 (generation of HBM data), WP7 (data formatting and data organisation) and T8.3 (integrative model development). Links outside PARC  HBM4EU legacy: the project will build further on experiences, results, materials, and networks developed within HBM4EU  EuroMix legacy and EuroMix follow-up: make use of the MCRA software developed in the EuroMix project  Green Deal projects addressing PFAS and mixtures (e.g., awarded projects as PANORAMIX for mixtures) and SPRINT (pesticides).  EFSA RACEMIC Roadmap for the Risk Assessment of Combined Exposure to Multiple Chemicals.  DG SANTE and EFSA-RIVM partnership on Regulatory implementation of dietary risk assessment of pesticide mixtures.  OECD activity effect biomarkers/AOPs PARC – ANNEX I AWPY3 – page 271 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.8 AWPY3 including PARC Project Portfolio OO10: As the project will use data that are generated outside PARC and by other PARC projects, and will generate data that can be used by other activities in and outside of PARC, implementation of FAIR data practices is a prerequisite. Links within PARC (WPs/Tasks/Activities/Projects)  WP2 for prioritization  WP3 for stakeholder consultation and communication  Use of existing data in cooperation with WP3 and data generated in WP4, WP5 and other T6.2 activities  Data sharing options and integrative model tools provided by WP7 and WP8  Projects inside PARC: o P6.2.4.a: Collection and generation of data for HIA of PARC priority chemicals o P6.2.4.b: Improvement of health impact assessment methodologies o P6.2.4.d: Development of a set of risk and health impact indicators o Projects from other WPs/Tasks to be identified Links outside PARC Projects generating quantitative chemical exposures and effects data e.g. ATHLETE, EXPANSE, NHANES, HEALS, NEUROSOME Key PARC Deliverables and Milestones to which the project contributes D6.4. 1st Report on health impact indicators and their policy implications (M36) AD6.6 (AWP Y1) Inventory of existing HIA, exposure and exposure-effect data for chemicals prioritised in PARC (M12) Partners List: ANSES (FR); AUTH (EL); BPI (EL); DTU (DK); ENSP (PT); FMUL (PT); IISPV (ES); INSA (PT); KI (SE); NIPH (NO); OI (SI); SRU (NL); Sciensano (BE); STAMI (NO); UU-IRAS (NL); VITO (BE) Schedule for the first part of the project: Starting date: 01/05/2022 (M1) Expected ending date: 31/10/2025 (M42) Costs: Expected PM for the third year of the project: 28 PM Expected ODC for the third year of the project: 3 875 € P6.2.4.d_Y1_HIAIndicators_VITO Project Title Development of a set of risk and health impact indicators Project Acronym (15 letters max) HIAIndicators Project Manager Jurgen Buekers jurge[email protected] VITO BE Deputy Project manager Jelle Vlaanderen [email protected] UU-IRAS NL Expected starting date PARC (Month number) 1 Expected duration 42* PARC Workpackage number 6 PARC Task/Activity/Subactivity: 6.2.4 Project Id P6.2.4.d_Y1_HIAIndicators_VITO * The project has been broken at mid-term (M42) to assess what has been achieved at the mid-term and if [Document text truncated for crawler view.]